bims-mitmed 2022-11-13 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–11–13
39 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
Heteroplasmic Mutant Load Differences in Mitochondrial DNA-Associated Leigh Syndrome.
Mitochondrial Epilepsy, a Challenge for Neurologists.
Mitochondrial Dysfunction as an Underlying Cause of Skeletal Muscle Disorders.
Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective.
Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission.
Ubiquitin-mediated mitochondrial regulation by MITOL/MARCHF5 at a glance.
Mitochondrial dynamics, Leydig cell function, and age-related testosterone deficiency.
Randomized trial of bilateral gene therapy injection for m.11778G > A MT-ND4 Leber optic neuropathy.
Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect.
Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in Caenorhabditis elegans.
Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration.
Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes.
The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer's Disease.
Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson's disease.
Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.
Tissue imaging reveals disruption of epithelial mitochondrial networks and loss of mitochondria-associated cytochrome-C in inflamed human and murine colon.
Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function.
Prediction of the disease course in Friedreich ataxia.
Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.
Novel protein complexes containing autophagy and UPS components regulate proteasome-dependent PARK2 recruitment onto mitochondria and PARK2-PARK6 activity during mitophagy.
Mitochondrial Cardiomyopathy: The Roles of mt-tRNA Mutations.
Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing.
Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren's Syndrome.
Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1.
Mitochondrial haplogroups and cognitive progression in Parkinson's disease.
Modulating autophagy and mitophagy as a promising therapeutic approach in neurodegenerative disorders.
Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle.
Does oxidative DNA damage trigger histotoxic hypoxia via PARP1/AMP-driven mitochondrial ADP depletion-induced ATP synthase inhibition in Alzheimer's disease?
Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts.
Rare and common genetic determinants of metabolic individuality and their effects on human health.
Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.
Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila.
A Rare Case of Type B Neonatal Pyruvate Carboxylase Enzyme Deficiency Presenting With Refractory Lactic Acidosis in the Early Neonatal Period.
Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity.
Porcine placental extract increase the cellular NAD levels in human epidermal keratinocytes.
Mitochondrial Transplantation Moderately Ameliorates Retinal Degeneration in Royal College of Surgeons Rats.
Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.

Sci Adv. 2022 Nov 11. 8(45): eabo7956

AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.

Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.

Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.

DOI: https://doi.org/10.1126/sciadv.abo7956
Nat Commun. 2022 Nov 07. 13(1): 6704

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.

Ayesha Sen, Sebastian Kallabis, Felix Gaedke, Christian Jüngst, Julia Boix, Julian Nüchel, Kanjanamas Maliphol, Julia Hofmann, Astrid C Schauss, Marcus Krüger, Rudolf J Wiesner, David Pla-Martín.

Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.

DOI: https://doi.org/10.1038/s41467-022-34205-9
Pediatr Neurol. 2022 Oct 05. pii: S0887-8994(22)00207-7. [Epub ahead of print]138 27-32

Heteroplasmic Mutant Load Differences in Mitochondrial DNA-Associated Leigh Syndrome.

Ji-Hoon Na, Young-Mock Lee.

   BACKGROUND: Mitochondrial DNA (mtDNA)-associated Leigh syndrome is influenced by mutant pathogenicity and corresponding heteroplasmic loads; however, the manner in which heteroplasmic mutant load affects patient phenotypes and the relationship between mutant types and heteroplasmic mutant loads remain unknown. We aimed to investigate the distribution of the mutant load of different mtDNA mutations in a single-center cohort.
METHODS: We used next-generation sequencing to confirm mtDNA mutations in 31 patients with Leigh syndrome. Subsequently, we counted the number of mtDNA reads to quantitatively analyze the heteroplasmic mutant load and categorize the patients according to the mtDNA mutations they harbored. Confirmed cases of mtDNA-associated Leigh syndrome were classified according to the mutations observed in six genes and 10 nucleotides.
RESULTS: Of the 31 patients with Leigh syndrome, 27 harbored known pathogenic mutations. We discovered that MT-ATP6 was the most commonly mutated gene (n = 13 patients), followed by MT-ND3 (n = 7) and MT-ND5 (n = 4). MT-ATP6 had a significantly higher mutant load than MT-ND3 and MT-ND5 (P < 0.001, each). By contrast, MT-ND5 had a significantly lower mutant load than MT-ND3 (P = 0.007). Notably, the mutation loads varied significantly among patients carrying the MT-ATP6, MT-ND3, and MT-ND5 mutations.
CONCLUSIONS: Our study illustrated the heteroplasmic diversity and phenotypic expression threshold of mutated mitochondrial genes in mtDNA-associated Leigh syndrome. The results provide promising insights into the genotype-phenotype correlation in mtDNA-associated Leigh syndrome that are expected to guide the development of tailored treatments for Leigh syndrome.

Keywords:  Heteroplasmic mutation; Heteroplasmy; Leigh syndrome; Mitochondrial DNA; Mitochondrial diseases

DOI:  https://doi.org/10.1016/j.pediatrneurol.2022.09.006
Int J Mol Sci. 2022 Oct 30. pii: 13216. [Epub ahead of print]23(21):

Mitochondrial Epilepsy, a Challenge for Neurologists.

Piervito Lopriore, Fábio Gomes, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso.

  Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.

Keywords:  Leigh syndrome; MELAS; MERRF; POLG-related disorders; epilepsy; mitochondrial epilepsy; primary mitochondrial disease; stroke-like episode

DOI:  https://doi.org/10.3390/ijms232113216
Int J Mol Sci. 2022 Oct 26. pii: 12926. [Epub ahead of print]23(21):

Mitochondrial Dysfunction as an Underlying Cause of Skeletal Muscle Disorders.

Tsung-Hsien Chen, Kok-Yean Koh, Kurt Ming-Chao Lin, Chu-Kuang Chou.

  Mitochondria are an important energy source in skeletal muscle. A main function of mitochondria is the generation of ATP for energy through oxidative phosphorylation (OXPHOS). Mitochondrial defects or abnormalities can lead to muscle disease or multisystem disease. Mitochondrial dysfunction can be caused by defective mitochondrial OXPHOS, mtDNA mutations, Ca2+ imbalances, mitochondrial-related proteins, mitochondrial chaperone proteins, and ultrastructural defects. In addition, an imbalance between mitochondrial fusion and fission, lysosomal dysfunction due to insufficient biosynthesis, and/or defects in mitophagy can result in mitochondrial damage. In this review, we explore the association between impaired mitochondrial function and skeletal muscle disorders. Furthermore, we emphasize the need for more research to determine the specific clinical benefits of mitochondrial therapy in the treatment of skeletal muscle disorders.

Keywords:  OXPHOS; mitochondrial chaperone protein; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; mtDNA mutation; skeletal muscle disorders

DOI:  https://doi.org/10.3390/ijms232112926
Biomolecules. 2022 Oct 29. pii: 1595. [Epub ahead of print]12(11):

Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective.

Jara Tabitha Hees, Angelika Bettina Harbauer.

  Neurons critically depend on mitochondria for ATP production and Ca2+ buffering. They are highly compartmentalized cells and therefore a finely tuned mitochondrial network constantly adapting to the local requirements is necessary. For neuronal maintenance, old or damaged mitochondria need to be degraded, while the functional mitochondrial pool needs to be replenished with freshly synthesized components. Mitochondrial biogenesis is known to be primarily regulated via the PGC-1α-NRF1/2-TFAM pathway at the transcriptional level. However, while transcriptional regulation of mitochondrial genes can change the global mitochondrial content in neurons, it does not explain how a morphologically complex cell such as a neuron adapts to local differences in mitochondrial demand. In this review, we discuss regulatory mechanisms controlling mitochondrial biogenesis thereby making a case for differential regulation at the transcriptional and translational level. In neurons, additional regulation can occur due to the axonal localization of mRNAs encoding mitochondrial proteins. Hitchhiking of mRNAs on organelles including mitochondria as well as contact site formation between mitochondria and endolysosomes are required for local mitochondrial biogenesis in axons linking defects in any of these organelles to the mitochondrial dysfunction seen in various neurological disorders.

Keywords:  AMPK; PGC-1α; insulin; mTORC1; mitochondrial biogenesis; neurons; transcription; translation

DOI:  https://doi.org/10.3390/biom12111595
Front Cell Dev Biol. 2022 ;10 1010232

Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission.

Adam Green, Tanvir Hossain, David M Eckmann.

  Mitochondria are cell organelles that play pivotal roles in maintaining cell survival, cellular metabolic homeostasis, and cell death. Mitochondria are highly dynamic entities which undergo fusion and fission, and have been shown to be very motile in vivo in neurons and in vitro in multiple cell lines. Fusion and fission are essential for maintaining mitochondrial homeostasis through control of morphology, content exchange, inheritance of mitochondria, maintenance of mitochondrial DNA, and removal of damaged mitochondria by autophagy. Mitochondrial motility occurs through mechanical and molecular mechanisms which translocate mitochondria to sites of high energy demand. Motility also plays an important role in intracellular signaling. Here, we review key features that mediate mitochondrial dynamics and explore methods to advance the study of mitochondrial motility as well as mitochondrial dynamics-related diseases and mitochondrial-targeted therapeutics.

Keywords:  disease; fission; fusion; live-cell imaging; mitochondria; mitochondrial DNA; motility; therapeutics

DOI:  https://doi.org/10.3389/fcell.2022.1010232
J Biochem. 2022 Nov 08. pii: mvac092. [Epub ahead of print]

Ubiquitin-mediated mitochondrial regulation by MITOL/MARCHF5 at a glance.

Shun Nagashima, Naoki Ito, Isshin Shiiba, Hiroki Shimura, Shigeru Yanagi.

  Mitochondria are involved in various cellular processes, such as energy production, inflammatory responses, and cell death. Mitochondrial dysfunction is associated with many age-related diseases, including neurological disorders and heart failure. Mitochondrial quality is strictly maintained by mitochondrial dynamics linked to an adequate supply of phospholipids and other substances from the endoplasmic reticulum (ER). The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 is responsible for mitochondrial quality control through the regulation of mitochondrial dynamics, formation of mitochondria-ER contacts, and mitophagy. MITOL deficiency has been shown to impair mitochondrial function, cause an excessive inflammatory response, and increase vulnerability to stress, resulting in the exacerbation of the disease. In this study, we overview the ubiquitin-mediated regulation of mitochondrial function by MITOL and the relationship between MITOL and diseases.

Keywords:  MITOL/MARCHF5; mitochondria; mitochondria-ER contacts; mitochondrial dynamics; ubiquitin

DOI:  https://doi.org/10.1093/jb/mvac092
FASEB J. 2022 Dec;36(12): e22637

Mitochondrial dynamics, Leydig cell function, and age-related testosterone deficiency.

Samuel Garza, Liting Chen, Melanie Galano, Garett Cheung, Chantal Sottas, Lu Li, Yuchang Li, Barry R Zirkin, Vassilios Papadopoulos.

  The mitochondrial translocator protein (18 kDa; TSPO) is a high-affinity cholesterol-binding protein that is an integral component of the cholesterol trafficking scaffold responsible for determining the rate of cholesterol import into the mitochondria for steroid biosynthesis. Previous studies have shown that TSPO declines in aging Leydig cells (LCs) and that its decline is associated with depressed circulating testosterone levels in aging rats. However, TSPO's role in the mechanistic decline in LC function is not fully understood. To address the role of TSPO depletion in LC function, we first examined mitochondrial quality in Tspo knockout mouse tumor MA-10 nG1 LCs compared to wild-type MA-10 cells. Tspo deletion caused a disruption in mitochondrial function and membrane dynamics. Increasing mitochondrial fusion via treatment with the mitochondrial fusion promoter M1 or by optic atrophy 1 (OPA1) overexpression resulted in the restoration of mitochondrial function and mitochondrial morphology as well as in steroid formation in TSPO-depleted nG1 LCs. LCs isolated from aged rats form less testosterone than LCs isolated from young rats. Treatment of aging LCs with M1 improved mitochondrial function and increased androgen formation, suggesting that aging LC dysfunction may stem from compromised mitochondrial dynamics caused by the age-dependent LC TSPO decline. These results, taken together, suggest that maintaining or enhancing mitochondrial fusion may provide therapeutic strategies to maintain or restore testosterone levels with aging.

Keywords:  aging; bioenergetics; hypogonadism; mitochondrial fusion; optic atrophy 1; steroidogenesis; testosterone; translocator protein

DOI:  https://doi.org/10.1096/fj.202201026R
Brain. 2022 Nov 09. pii: awac421. [Epub ahead of print]

Randomized trial of bilateral gene therapy injection for m.11778G > A MT-ND4 Leber optic neuropathy.

LHON REFLECT Study Group

  Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G > A mutation in the MT-ND4 gene being the most common disease-causing mitochondrial DNA (mtDNA) variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G > A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary endpoint was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary endpoint). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (p < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (p < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G > A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Keywords:  Leber hereditary optic neuropathy; NADH dehydrogenase 4; lenadogene nolparvovec; mitochondrial DNA; recombinant adeno-associated virus vector 2

DOI:  https://doi.org/10.1093/brain/awac421
Brain. 2022 Nov 09. pii: awac417. [Epub ahead of print]

Neuropathological hallmarks of antenatal mitochondrial diseases with a corpus callosum defect.

Lucile Boutaud, Benedetta Ruzzenente, Aude Tessier, Olivia Anselem, Emmanuelle Pannier, Sarah Grotto, Naïma Talhi, Daniel Amram, Marjolaine Willems, Constance Wells, Patricia Blanchet, Yuri Musizzano, Clémence Jauny, Patrick Nitschke, Christine Bole-Feysot, Bettina Bessières, Houria Salhi, Amale Achaiaa, Metodi D Metodiev, Ferechte Razavi, Agnès Rötig, Laurence Loeuilllet, Tania Attié-Bitach.

  Corpus callosum defects are frequent congenital cerebral disorders caused by mutations in more than 300 genes. These include genes implicated in corpus callosum development or function, as well as genes essential for mitochondrial physiology. However, in utero corpus callosum anomalies rarely raise a suspicion of mitochondrial disease and are characterized by a very large clinical heterogeneity. Here, we report a detailed pathological and neuro-histopathological investigation of 9 fetuses from 4 unrelated families with prenatal onset of corpus callosum anomalies, sometimes associated with other cerebral or extra-cerebral defects. Next generation sequencing allowed the identification of novel pathogenic variants in 3 different nuclear genes previously reported in mitochondrial diseases: TIMMDC1, encoding a complex I assembly factor never involved before in corpus callosum defect; MRPS22, a protein of the small mitoribosomal subunit, and EARS2, the mitochondrial tRNA-glutamyl synthetase. The present report describes the antenatal histopathological findings in mitochondrial diseases and expands the genetic spectrum of antenatal corpus callosum anomalies establishing OXPHOS function as an important factor for corpus callosum biogenesis. We propose that, when observed, antenatal corpus callosum anomalies should raise suspicion of mitochondrial disease and prenatal genetic counseling should be considered.

Keywords:   EARS2 ; MRSP22 ; TIMMDC1 ; corpus callosum defect; mitochondrial diseases

DOI:  https://doi.org/10.1093/brain/awac417
Genetics. 2022 Nov 02. pii: iyac160. [Epub ahead of print]

Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in Caenorhabditis elegans.

Cole M Haynes, Siegfried Hekimi.

  We review the findings that establish that perturbations of various aspects of mitochondrial function, including oxidative phosphorylation, can promote lifespan extension, with different types of perturbations acting sometimes independently and additively on extending lifespan. We also review the great variety of processes and mechanisms that together form the mitochondrial unfolded protein response. We then explore the relationships between different types of mitochondrial dysfunction-dependent lifespan extension and the mitochondrial unfolded protein response. We conclude that, although several ways that induce extended lifespan through mitochondrial dysfunction require a functional mitochondrial unfolded protein response, there is no clear indication that activation of the mitochondrial unfolded protein response is sufficient to extend lifespan, despite the fact that the mitochondrial unfolded protein response impacts almost every aspect of mitochondrial function. In fact, in some contexts, mitochondrial unfolded protein response activation is deleterious. To explain this pattern, we hypothesize that, although triggered by mitochondrial dysfunction, the lifespan extension observed might not be the result of a change in mitochondrial function.

Keywords:  UPRmt; WormBook; aging; mitochondria

DOI:  https://doi.org/10.1093/genetics/iyac160
Nat Commun. 2022 Nov 11. 13(1): 6869

Impaired mitochondrial oxidative metabolism in skeletal progenitor cells leads to musculoskeletal disintegration.

Chujiao Lin, Qiyuan Yang, Dongsheng Guo, Jun Xie, Yeon-Suk Yang, Sachin Chaugule, Ngoc DeSouza, Won-Taek Oh, Rui Li, Zhihao Chen, Aijaz A John, Qiang Qiu, Lihua Julie Zhu, Matthew B Greenblatt, Sankar Ghosh, Shaoguang Li, Guangping Gao, Cole Haynes, Charles P Emerson, Jae-Hyuck Shim.

Although skeletal progenitors provide a reservoir for bone-forming osteoblasts, the major energy source for their osteogenesis remains unclear. Here, we demonstrate a requirement for mitochondrial oxidative phosphorylation in the osteogenic commitment and differentiation of skeletal progenitors. Deletion of Evolutionarily Conserved Signaling Intermediate in Toll pathways (ECSIT) in skeletal progenitors hinders bone formation and regeneration, resulting in skeletal deformity, defects in the bone marrow niche and spontaneous fractures followed by persistent nonunion. Upon skeletal fracture, Ecsit-deficient skeletal progenitors migrate to adjacent skeletal muscle causing muscle atrophy. These phenotypes are intrinsic to ECSIT function in skeletal progenitors, as little skeletal abnormalities were observed in mice lacking Ecsit in committed osteoprogenitors or mature osteoblasts. Mechanistically, Ecsit deletion in skeletal progenitors impairs mitochondrial complex assembly and mitochondrial oxidative phosphorylation and elevates glycolysis. ECSIT-associated skeletal phenotypes were reversed by in vivo reconstitution with wild-type ECSIT expression, but not a mutant displaying defective mitochondrial localization. Collectively, these findings identify mitochondrial oxidative phosphorylation as the prominent energy-driving force for osteogenesis of skeletal progenitors, governing musculoskeletal integrity.

DOI: https://doi.org/10.1038/s41467-022-34694-8
Mol Genet Genomic Med. 2022 Nov 11. e2093

Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes.

Mariana B Angulo, Alexander Bertalovitz, Mariana A Argenziano, Jiajia Yang, Aarti Patel, Theresa Zesiewicz, Thomas V McDonald.

   BACKGROUND: Friedreich's ataxia (FRDA) is an autosomal recessive disease, whereby homozygous inheritance of an expanded GAA trinucleotide repeat expansion in the first intron of the FXN gene leads to transcriptional repression of the encoded protein frataxin. FRDA is a progressive neurodegenerative disorder, but the primary cause of death is heart disease which occurs in 60% of the patients. Several functions of frataxin have been proposed, but none of them fully explain why its deficiency causes the FRDA phenotypes nor why the most affected cell types are neurons and cardiomyocytes.
METHODS: To investigate, we generated iPSC-derived neurons (iNs) and cardiomyocytes (iCMs) from an FRDA patient and upregulated FXN expression via lentivirus without altering genomic GAA repeats at the FXN locus.
RESULTS: RNA-seq and differential gene expression enrichment analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathway genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FRDA cells were supplemented with frataxin.
CONCLUSIONS: These results offer novel insight into specific roles of frataxin deficiency pathogenesis in neurons and cardiomyocytes.

Keywords:  Friedreich's ataxia; extracellular matrix; frataxin; glycolysis; lentivirus

DOI:  https://doi.org/10.1002/mgg3.2093
Acta Naturae. 2022 Jul-Sep;14(3):14(3): 19-34

The Role of a Pathological Interaction between β-amyloid and Mitochondria in the Occurrence and Development of Alzheimer's Disease.

N S Nikolaeva, E Yu Yandulova, Yu R Aleksandrova, A S Starikov, M E Neganova.

  Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in existence. It is characterized by an impaired cognitive function that is due to a progressive loss of neurons in the brain. Extracellular β-amyloid (Aβ) plaques are the main pathological features of the disease. In addition to abnormal protein aggregation, increased mitochondrial fragmentation, altered expression of the genes involved in mitochondrial biogenesis, disruptions in the ER-mitochondria interaction, and mitophagy are observed. Reactive oxygen species are known to affect Aβ expression and aggregation. In turn, oligomeric and aggregated Aβ cause mitochondrial disorders. In this review, we summarize available knowledge about the pathological effects of Aβ on mitochondria and the potential molecular targets associated with proteinopathy and mitochondrial dysfunction for the pharmacological treatment of Alzheimer's disease.

Keywords:  Alzheimer’s disease; MAM; beta-amyloid; mitochondria; mitophagy

DOI:  https://doi.org/10.32607/actanaturae.11723
Front Aging Neurosci. 2022 ;14 986849

Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson's disease.

Jyotsna Asthana, Bhupendra V Shravage.

  Parkinson's disease (PD) is the second most popular age-associated neurodegenerative disorder after Alzheimer's disease. The degeneration of dopaminergic neurons, aggregation of α-synuclein (α-syn), and locomotor defects are the main characteristic features of PD. The main cause of a familial form of PD is associated with a mutation in genes such as SNCA, PINK1, Parkin, DJ-1, LRKK2, and others. Recent advances have uncovered the different underlying mechanisms of PD but the treatment of PD is still unknown due to the unavailability of effective therapies and preventive medicines in the current scenario. The pathophysiology and genetics of PD have been strongly associated with mitochondria in disease etiology. Several studies have investigated a complex molecular mechanism governing the identification and clearance of dysfunctional mitochondria from the cell, a mitochondrial quality control mechanism called mitophagy. Reduced mitophagy and mitochondrial impairment are found in both sporadic and familial PD. Pharmacologically modulating mitophagy and accelerating the removal of defective mitochondria are of common interest in developing a therapy for PD. However, despite the extensive understanding of the mitochondrial quality control pathway and its underlying mechanism, the therapeutic potential of targeting mitophagy modulation and its role in PD remains to be explored. Thus, targeting mitophagy using chemical agents and naturally occurring phytochemicals could be an emerging therapeutic strategy in PD prevention and treatment. We discuss the current research on understanding the role of mitophagy modulators in PD using Drosophila melanogaster as a model. We further explore the contribution of Drosophila in the pathophysiology of PD, and discuss comprehensive genetic analysis in flies and pharmacological drug screening to develop potential therapeutic molecules for PD.

Keywords:  Drosophila; Mitophagy; Parkinson’s disease; mitochondria; neurodegenerative disorder

DOI:  https://doi.org/10.3389/fnagi.2022.986849
iScience. 2022 Nov 18. 25(11): 105342

Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.

Neeraja Purandare, Yusef Kunji, Yue Xi, Roberto Romero, Nardhy Gomez-Lopez, Andrew Fribley, Lawrence I Grossman, Siddhesh Aras.

  Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammation in pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a bi-organellar protein responsible for mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of systemic placental inflammation, we show that MNRR1 levels are reduced both in mouse placental tissues in vivo and in human trophoblastic cell lines in vitro. MNRR1 reduction is associated with mitochondrial dysfunction, enhanced oxidative stress, and activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in ATM kinase-dependent threonine phosphorylation that stabilizes mitochondrial protease YME1L1, which targets MNRR1. Enhancing MNRR1 levels abrogates the bioenergetic defect and induces an anti-inflammatory phenotype. We therefore propose MNRR1 as an anti-inflammatory therapeutic in placental inflammation.

Keywords:  Cell biology; Human metabolism; Immunity

DOI:  https://doi.org/10.1016/j.isci.2022.105342
Mitochondrion. 2022 Nov 07. pii: S1567-7249(22)00088-5. [Epub ahead of print]

Tissue imaging reveals disruption of epithelial mitochondrial networks and loss of mitochondria-associated cytochrome-C in inflamed human and murine colon.

Andrew K Chojnacki, Saranya Navaneetha Krishnan, Humberto Jijon, Timothy E Shutt, Pina Colarusso, Derek M McKay.

  Mitochondrial dysfunction as defined by transcriptomic and proteomic analysis of biopsies or ultra-structure in transmission electron microscopy occurs in inflammatory bowel disease (IBD); however, mitochondrial dynamics in IBD have received minimal attention, with most investigations relying on cell-based in vitro models. We build on these studies by adapting the epithelial cell immunofluorescence workflow to imaging mitochondrial networks in normal and inflamed colonic tissue (i.e., murine di-nitrobenzene sulphonic acid (DNBS)-induced colitis, human ulcerative colitis). Using antibodies directed to TOMM20 (translocase of outer mitochondrial membrane 20) and cytochrome-C, we have translated the cell-based protocol for high-fidelity imaging to examine epithelial mitochondria networks in intact intestine. In epithelia of non-inflamed small or large intestinal tissue, the mitochondrial networks were dense and compact. This pattern was more pronounced in the basal region of the cell compared to that between the nucleus and apical surface facing the gut lumen. In comparison, mitochondrial networks in inflamed tissue displayed substantial loss of TOMM20+ staining. The remaining networks were less dense and fragmented, and contained isolated spherical mitochondrial fragments. The degree of mitochondrial network fragmentation mirrored the severity of inflammation, as assessed by blinded semi-quantitative scoring. As an indication of poor cell 'health' or viability, cytosolic cytochrome-C was observed in enterocytes with highly fragmented mitochondria. Thus, high-resolution and detailed visualization of mitochondrial networks in tissue is a feasible and valuable approach to assess disease, suited to characterizing mitochondrial abnormalities in tissue. We speculate that drugs that maintain a functional remodelling mitochondrial network and limit excess fragmentation could be a valuable addition to current therapies for IBD.

Keywords:  IBD; TOMM20; epithelium; in situ tissue imaging; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.mito.2022.10.004
Front Pharmacol. 2022 ;13 947387

Adenosine monophosphate activated protein kinase contributes to skeletal muscle health through the control of mitochondrial function.

Yan Yan, Ming Li, Jie Lin, Yanan Ji, Kexin Wang, Dajun Yan, Yuntian Shen, Wei Wang, Zhongwei Huang, Haiyan Jiang, Hualin Sun, Lei Qi.

  Skeletal muscle is one of the largest organs in the body and the largest protein repository. Mitochondria are the main energy-producing organelles in cells and play an important role in skeletal muscle health and function. They participate in several biological processes related to skeletal muscle metabolism, growth, and regeneration. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor and regulator of systemic energy balance. AMPK is involved in the control of energy metabolism by regulating many downstream targets. In this review, we propose that AMPK directly controls several facets of mitochondrial function, which in turn controls skeletal muscle metabolism and health. This review is divided into four parts. First, we summarize the properties of AMPK signal transduction and its upstream activators. Second, we discuss the role of mitochondria in myogenesis, muscle atrophy, regeneration post-injury of skeletal muscle cells. Third, we elaborate the effects of AMPK on mitochondrial biogenesis, fusion, fission and mitochondrial autophagy, and discuss how AMPK regulates the metabolism of skeletal muscle by regulating mitochondrial function. Finally, we discuss the effects of AMPK activators on muscle disease status. This review thus represents a foundation for understanding this biological process of mitochondrial dynamics regulated by AMPK in the metabolism of skeletal muscle. A better understanding of the role of AMPK on mitochondrial dynamic is essential to improve mitochondrial function, and hence promote skeletal muscle health and function.

Keywords:  AMPK; mitochondria; muscle atrophy; muscle regeneration; skeletal muscle

DOI:  https://doi.org/10.3389/fphar.2022.947387
Sci Rep. 2022 Nov 10. 12(1): 19173

Prediction of the disease course in Friedreich ataxia.

Christian Hohenfeld, Ulrich Terstiege, Imis Dogan, Paola Giunti, Michael H Parkinson, Caterina Mariotti, Lorenzo Nanetti, Mario Fichera, Alexandra Durr, Claire Ewenczyk, Sylvia Boesch, Wolfgang Nachbauer, Thomas Klopstock, Claudia Stendel, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Stefanie N Hayer, Thomas Klockgether, Ilaria Giordano, Claire Didszun, Myriam Rai, Massimo Pandolfo, Holger Rauhut, Jörg B Schulz, Kathrin Reetz.

We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.

DOI: https://doi.org/10.1038/s41598-022-23666-z
Nat Commun. 2022 Nov 11. 13(1): 6830

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.

Kan Xie, Helmut Fuchs, Enzo Scifo, Dan Liu, Ahmad Aziz, Juan Antonio Aguilar-Pimentel, Oana Veronica Amarie, Lore Becker, Patricia da Silva-Buttkus, Julia Calzada-Wack, Yi-Li Cho, Yushuang Deng, A Cole Edwards, Lillian Garrett, Christina Georgopoulou, Raffaele Gerlini, Sabine M Hölter, Tanja Klein-Rodewald, Michael Kramer, Stefanie Leuchtenberger, Dimitra Lountzi, Phillip Mayer-Kuckuk, Lena L Nover, Manuela A Oestereicher, Clemens Overkott, Brandon L Pearson, Birgit Rathkolb, Jan Rozman, Jenny Russ, Kristina Schaaf, Nadine Spielmann, Adrián Sanz-Moreno, Claudia Stoeger, Irina Treise, Daniele Bano, Dirk H Busch, Jochen Graw, Martin Klingenspor, Thomas Klopstock, Beverly A Mock, Paolo Salomoni, Carsten Schmidt-Weber, Marco Weiergräber, Eckhard Wolf, Wolfgang Wurst, Valérie Gailus-Durner, Monique M B Breteler, Martin Hrabě de Angelis, Dan Ehninger.

Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.

DOI: https://doi.org/10.1038/s41467-022-34515-y
Cell Death Dis. 2022 Nov 10. 13(11): 947

Novel protein complexes containing autophagy and UPS components regulate proteasome-dependent PARK2 recruitment onto mitochondria and PARK2-PARK6 activity during mitophagy.

Nur Mehpare Kocaturk, Nesibe Peker, Karin Eberhart, Yunus Akkoc, Gamze Deveci, Joern Dengjel, Devrim Gozuacik.

Autophagy is an evolutionarily conserved eukaryotic cellular mechanism through which cytosolic fragments, misfolded/aggregated proteins and organelles are degraded and recycled. Priming of mitochondria through ubiquitylation is required for the clearance the organelle by autophagy (mitophagy). Familial Parkinson's Disease-related proteins, including the E3-ligase PARK2 (PARKIN) and the serine/threonine kinase PARK6 (PINK1) control these ubiquitylation reactions and contribute to the regulation of mitophagy. Here we describe, novel protein complexes containing autophagy protein ATG5 and ubiquitin-proteasome system (UPS) components. We discovered that ATG5 interacts with PSMA7 and PARK2 upon mitochondrial stress. Results suggest that all three proteins translocate mitochondria and involve in protein complexes containing autophagy, UPS and mitophagy proteins. Interestingly, PARK2 and ATG5 recruitment onto mitochondria requires proteasome components PSMA7 and PSMB5. Strikingly, we discovered that subunit of 20 S proteasome, PSMA7, is required for the progression of PARK2-PARK6-mediated mitophagy and the proteasome activity following mitochondrial stress. Our results demonstrate direct, dynamic and functional interactions between autophagy and UPS components that contribute to the regulation of mitophagy.

DOI: https://doi.org/10.1038/s41419-022-05339-x
J Clin Med. 2022 Oct 30. pii: 6431. [Epub ahead of print]11(21):

Mitochondrial Cardiomyopathy: The Roles of mt-tRNA Mutations.

Yu Ding, Beibei Gao, Jinyu Huang.

  Mitochondria are important organelles whose primary role is generating energy through the oxidative phosphorylation (OXPHOS) system. Cardiomyopathy, a common clinical disorder, is frequently associated with pathogenic mutations in nuclear and mitochondrial genes. To date, a growing number of nuclear gene mutations have been linked with cardiomyopathy; however, knowledge about mitochondrial tRNAs (mt-tRNAs) mutations in this disease remain inadequately understood. In fact, defects in mt-tRNA metabolism caused by pathogenic mutations may influence the functioning of the OXPHOS complexes, thereby impairing mitochondrial translation, which plays a critical role in the predisposition of this disease. In this review, we summarize some basic knowledge about tRNA biology, including its structure and function relations, modification, CCA-addition, and tRNA import into mitochondria. Furthermore, a variety of molecular mechanisms underlying tRNA mutations that cause mitochondrial dysfunctions are also discussed in this article.

Keywords:  OXPHOS system; cardiomyopathy; mt-tRNA; mutations; tRNA biology

DOI:  https://doi.org/10.3390/jcm11216431
Nat Commun. 2022 Nov 07. 13(1): 6324

Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing.

Genomics England Research Consortium

Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk .

DOI: https://doi.org/10.1038/s41467-022-32908-7
Biomedicines. 2022 Oct 25. pii: 2699. [Epub ahead of print]10(11):

Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren's Syndrome.

Giada De Benedittis, Andrea Latini, Serena Colafrancesco, Roberta Priori, Carlo Perricone, Lucia Novelli, Paola Borgiani, Cinzia Ciccacci.

  Sjögren's syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role in inflammatory and immune processes. Since the mitochondrial DNA (mtDNA) copy number could change in response to physiological or environmental stimuli, this study aimed to evaluate possible alterations in the mtDNA copy number in SS. We have analyzed the amount of mtDNA in the peripheral blood of 74 SS patients and 61 healthy controls by qPCR. Then, since mitochondrial fusion and fission play a crucial role in maintaining the number of mitochondria, we investigated the expression variability of the genes most commonly involved in mitochondrial dynamics in a subgroup of SS patients and healthy controls. Interestingly, we observed a highly significant decrease in mtDNA copies in the SS patients compared to healthy controls (p = 1.44 × 10-12). Expression levels of mitochondrial fission factor (MFF), mitofusin-1 (MFN1), and mitochondrial transcription factor A (TFAM) genes were analyzed, showing a statistically significant increase in the expression of MFF (p = 0.003) and TFAM (p = 0.022) in the SS patients compared to healthy controls. These results give further insight into the possible involvement of mitochondrial dysfunctions in SS disease.

Keywords:  Sjögren’s syndrome; mitochondrial dynamics; mtDNA; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines10112699
Brain. 2022 Nov 10. pii: awac422. [Epub ahead of print]

Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1.

Catarina Osório, Joshua J White, Heiling Lu, Gerrit C Beekhof, Francesca Romana Fiocchi, Charlotte A Andriessen, Stephanie Dijkhuizen, Laura Post, Martijn Schonewille.

  Spinocerebellar ataxias are neurodegenerative diseases the hallmark symptom of which is the development of ataxia due to cerebellar dysfunction. Purkinje cells (PCs), the principal neurons of the cerebellar cortex, are the main cells affected in these disorders but the sequence of pathological events leading to their dysfunction is poorly understood. Understanding the origins of PC dysfunction before it manifests is imperative to interpret the functional and behavioural consequences of cerebellar-related disorders, providing an optimal timeline for therapeutic interventions. Here, we report the cascade of events leading to PC dysfunction before the onset of ataxia in a mouse model of spinocerebellar ataxia 1. Spatiotemporal characterisation of the ATXN1[82Q] SCA1 mouse model revealed high levels of the mutant ATXN1[82Q] weeks before the onset of ataxia. The expression of the toxic protein first caused a reduction of PC intrinsic excitability, which was followed by atrophy of PC dendrite arborisation and aberrant glutamatergic signalling, finally leading to disruption of PC innervation of climbing fibers (CFs) and loss of intrinsic plasticity of PCs. Functionally, we found that deficits in eyeblink conditioning, a form of cerebellum-dependent motor learning, precede the onset of ataxia, matching the timeline of CF degeneration and reduced intrinsic plasticity. Together, our results suggest that abnormal synaptic signalling and intrinsic plasticity during the pre-ataxia stage of spinocerebellar ataxias underlie an aberrant cerebellar circuitry that anticipates the full extent of the disease severity. Furthermore, our work indicates the potential for eyeblink conditioning to be used as a sensitive tool to detect early cerebellar dysfunction as a sign of future disease.

Keywords:  Ataxin1; Purkinje cell; cerebellum; eyeblink conditioning; presymptomatic

DOI:  https://doi.org/10.1093/brain/awac422
Brain. 2022 Nov 08. pii: awac327. [Epub ahead of print]

Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

International Genetics of Parkinson Disease Progression (IGPP) Consortium

  Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Keywords:  Parkinson’s disease; cognitive progression; mitochondrial haplogroups

DOI:  https://doi.org/10.1093/brain/awac327
Life Sci. 2022 Nov 04. pii: S0024-3205(22)00853-0. [Epub ahead of print] 121153

Modulating autophagy and mitophagy as a promising therapeutic approach in neurodegenerative disorders.

Jayapriya Mishra, Gurjit Kaur Bhatti, Abhishek Sehrawat, Charan Singh, Arti Singh, Arubala P Reddy, P Hemachandra Reddy, Jasvinder Singh Bhatti.

  The high prevalence of neurodegenerative diseases has become a major public health challenge and is associated with a tremendous burden on individuals, society and federal governments worldwide. Protein misfolding and aggregation are the major pathological hallmarks of several neurodegenerative disorders. The cells have evolved several regulatory mechanisms to deal with aberrant protein folding, namely the classical ubiquitin pathway, where ubiquitination of protein aggregates marks their degradation via lysosome and the novel autophagy or mitophagy pathways. Autophagy is a catabolic process in eukaryotic cells that allows the lysosome to recycle the cell's own contents, such as organelles and proteins, known as autophagic cargo. Their most significant role is to keep cells alive in distressed situations. Mitophagy is also crucial for reducing abnormal protein aggregation and increasing organelle clearance and partly accounts for maintaining cellular homeostasis. Furthermore, substantial data indicate that any disruption in these homeostatic mechanisms leads to the emergence of several age-associated metabolic and neurodegenerative diseases. So, targeting autophagy and mitophagy might be a potential therapeutic strategy for a variety of health conditions.

Keywords:  Aggregation; Autophagic cargo; Autophagy; Functional foods; Homeostasis; Misfolding; Mitophagy; Neurodegenerative disorders

DOI:  https://doi.org/10.1016/j.lfs.2022.121153
Sci Rep. 2022 Nov 05. 12(1): 18776

Using a multiomics approach to unravel a septic shock specific signature in skeletal muscle.

Baptiste Duceau, Michael Blatzer, Jean Bardon, Thibault Chaze, Quentin Giai Gianetto, Florence Castelli, François Fenaille, Lucie Duarte, Thomas Lescot, Christophe Tresallet, Bruno Riou, Mariette Matondo, Olivier Langeron, Pierre Rocheteau, Fabrice Chrétien, Adrien Bouglé.

Sepsis is defined as a dysregulated host response to infection leading to organs failure. Among them, sepsis induces skeletal muscle (SM) alterations that contribute to acquired-weakness in critically ill patients. Proteomics and metabolomics could unravel biological mechanisms in sepsis-related organ dysfunction. Our objective was to characterize a distinctive signature of septic shock in human SM by using an integrative multi-omics approach. Muscle biopsies were obtained as part of a multicenter non-interventional prospective study. Study population included patients in septic shock (S group, with intra-abdominal source of sepsis) and two critically ill control populations: cardiogenic shock (C group) and brain dead (BD group). The proteins and metabolites were extracted and analyzed by High-Performance Liquid Chromatography-coupled to tandem Mass Spectrometry, respectively. Fifty patients were included, 19 for the S group (53% male, 64 ± 17 years, SAPS II 45 ± 14), 12 for the C group (75% male, 63 ± 4 years, SAPS II 43 ± 15), 19 for the BD group (63% male, 58 ± 10 years, SAPS II 58 ± 9). Biopsies were performed in median 3 days [interquartile range 1-4]) after intensive care unit admission. Respectively 31 patients and 40 patients were included in the proteomics and metabolomics analyses of 2264 proteins and 259 annotated metabolites. Enrichment analysis revealed that mitochondrial pathways were significantly decreased in the S group at protein level: oxidative phosphorylation (adjusted p = 0.008); branched chained amino acids degradation (adjusted p = 0.005); citrate cycle (adjusted p = 0.005); ketone body metabolism (adjusted p = 0.003) or fatty acid degradation (adjusted p = 0.008). Metabolic reprogramming was also suggested (i) by the differential abundance of the peroxisome proliferator-activated receptors signaling pathway (adjusted p = 0.007), and (ii) by the accumulation of fatty acids like octanedioic acid dimethyl or hydroxydecanoic. Increased polyamines and depletion of mitochondrial thioredoxin or mitochondrial peroxiredoxin indicated a high level of oxidative stress in the S group. Coordinated alterations in the proteomic and metabolomic profiles reveal a septic shock signature in SM, highlighting a global impairment of mitochondria-related metabolic pathways, the depletion of antioxidant capacities, and a metabolic shift towards lipid accumulation.ClinicalTrial registration: NCT02789995. Date of first registration 03/06/2016.

DOI: https://doi.org/10.1038/s41598-022-23544-8
Mitochondrion. 2022 Oct 29. pii: S1567-7249(22)00087-3. [Epub ahead of print]67 59-64

Does oxidative DNA damage trigger histotoxic hypoxia via PARP1/AMP-driven mitochondrial ADP depletion-induced ATP synthase inhibition in Alzheimer's disease?

Owen Davis Sanders, Lekshmy Rajagopal, Chandler Chase Barton, Jayalekshmi Archa Rajagopal, Olga Lopez, Kalei Lopez, Fayeza Malik.

  The low cerebral metabolic rate of oxygen despite the relatively preserved perfusion in Alzheimer's disease (AD) patients' medial temporal lobes suggest histotoxic hypoxia due to mitochondrial dysfunction that is independent of, but could precede, insulin resistance. Neuropathological, metabolomic, and preclinical evidence are consistent with the notion that this mitochondrial dysfunction may be contributed to by oxidative stress and DNA damage, leading to poly-(ADP-ribose)-polymerase-1 (PARP1) activation and consequent AMP accumulation, clogging of mitochondrial adenine nucleotide transporters (ANTs), matrix ADP deprivation, and ATP synthase inhibition. Complementary mechanisms may include mitochondrial-protein poly-ADP-ribosylation and mitochondrial-biogenesis suppression via PARPs outcompeting Sirtuin-1 (SIRT1) for nicotinamide-adenine-dinucleotide (NAD+).

Keywords:  DNA Damage; Insulin Resistance; Mitochondria; Oxidative Stress

DOI:  https://doi.org/10.1016/j.mito.2022.10.005
Front Neurosci. 2022 ;16 1009125

Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts.

Ioannis Angelopoulos, Georgios Gakis, Kyriakos Birmpas, Christina Kyrousi, Evagelia Eva Habeos, Konstantina Kaplani, Zoi Lygerou, Ioannis Habeos, Stavros Taraviras.

  The neural stem cell niche is a key regulator participating in the maintenance, regeneration, and repair of the brain. Within the niche neural stem cells (NSC) generate new neurons throughout life, which is important for tissue homeostasis and brain function. NSCs are regulated by intrinsic and extrinsic factors with cellular metabolism being lately recognized as one of the most important ones, with evidence suggesting that it may serve as a common signal integrator to ensure mammalian brain homeostasis. The aim of this review is to summarize recent insights into how metabolism affects NSC fate decisions in adult neural stem cell niches, with occasional referencing of embryonic neural stem cells when it is deemed necessary. Specifically, we will highlight the implication of mitochondria as crucial regulators of NSC fate decisions and the relationship between metabolism and ependymal cells. The link between primary cilia dysfunction in the region of hypothalamus and metabolic diseases will be examined as well. Lastly, the involvement of metabolic pathways in ependymal cell ciliogenesis and physiology regulation will be discussed.

Keywords:  cell mechanics; ciliopathies; ependymal; metabolism; neural stem cell niche; neural stem cells; subventricular zone (SVZ)

DOI:  https://doi.org/10.3389/fnins.2022.1009125
Nat Med. 2022 Nov 10.

Rare and common genetic determinants of metabolic individuality and their effects on human health.

Praveen Surendran, Isobel D Stewart, Victoria P W Au Yeung, Maik Pietzner, Johannes Raffler, Maria A Wörheide, Chen Li, Rebecca F Smith, Laura B L Wittemans, Lorenzo Bomba, Cristina Menni, Jonas Zierer, Niccolò Rossi, Patricia A Sheridan, Nicholas A Watkins, Massimo Mangino, Pirro G Hysi, Emanuele Di Angelantonio, Mario Falchi, Tim D Spector, Nicole Soranzo, Gregory A Michelotti, Wiebke Arlt, Luca A Lotta, Spiros Denaxas, Harry Hemingway, Eric R Gamazon, Joanna M M Howson, Angela M Wood, John Danesh, Nicholas J Wareham, Gabi Kastenmüller, Eric B Fauman, Karsten Suhre, Adam S Butterworth, Claudia Langenberg.

Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.

DOI: https://doi.org/10.1038/s41591-022-02046-0
Nat Commun. 2022 Nov 09. 13(1): 6779

Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.

Máté Katona, Ádám Bartók, Zuzana Nichtova, György Csordás, Elena Berezhnaya, David Weaver, Arijita Ghosh, Péter Várnai, David I Yule, György Hajnóczky.

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when 'parked', mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.

DOI: https://doi.org/10.1038/s41467-022-34365-8
Elife. 2022 Nov 08. pii: e82709. [Epub ahead of print]11

Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila.

Justin A Bosch, Berrak Ugur, Israel Pichardo-Casas, Jordan Rabasco, Felipe Escobedo, Zhongyuan Zuo, Ben Brown, Susan Celniker, David A Sinclair, Hugo J Bellen, Norbert Perrimon.

  Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of genes.

Keywords:  D. melanogaster; genetics; genomics; neuroscience

DOI:  https://doi.org/10.7554/eLife.82709
Cureus. 2022 Oct;14(10): e29903

A Rare Case of Type B Neonatal Pyruvate Carboxylase Enzyme Deficiency Presenting With Refractory Lactic Acidosis in the Early Neonatal Period.

Saima Sharif, Pradeep Kumar Velumula, Praveen Kumar Boddu, Deniz Altinok, Nithi Fernandes.

  Pyruvate carboxylase (PC) enzyme deficiency is a rare genetic disorder inherited in an autosomal recessive (AR) manner. PC, a mitochondrial enzyme, converts pyruvate to oxaloacetate (OAA), which enters the tricarboxylic acid (TCA) cycle. Based on the tissue type, intermediate metabolites of the TCA cycle play a vital role in gluconeogenesis, lipogenesis, synthesis of nicotinamide adenine dinucleotide phosphate (NADPH), and neurotransmitter glutamate in the astrocytes. The severity of clinical presentation depends on the type of PC deficiency and on the residual enzyme activity. We present a term female infant admitted with refractory lactic acidosis that developed soon after birth. On biochemical evaluation, serum ammonia was 125 µmol/L; plasma amino acid analysis showed elevated citrulline, lysine, proline, decreased glutamine, and aspartic acid; urine organic acid analysis showed markedly increased lactic acid, and moderately elevated 3-hydroxy-butyric and acetoacetic acid. MRI brain demonstrated abnormal diffuse white matter edema, loculated and septate large cysts along the caudothalamic notch as well as lateral aspect of the frontal horn bilaterally. Magnetic resonance (MR) spectroscopy showed large amounts of lactate peak. Molecular genetic analysis showed two pathogenic variants in the PC gene confirming the diagnosis of PC enzyme deficiency. The infant was discharged home on palliative and hospice care, and she died on the 22nd day after birth.

Keywords:  acidosis lactic; lactate peak; magnetic resonance spectroscopy (mrs); pyruvate carboxylase; pyruvate carboxylase enzyme deficiency; term neonate

DOI:  https://doi.org/10.7759/cureus.29903
Nat Biotechnol. 2022 Nov 10.

Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity.

Monica E Neugebauer, Alvin Hsu, Mandana Arbab, Nicholas A Krasnow, Amber N McElroy, Smriti Pandey, Jordan L Doman, Tony P Huang, Aditya Raguram, Samagya Banskota, Gregory A Newby, Jakub Tolar, Mark J Osborn, David R Liu.

Cytosine base editors (CBEs) are larger and can suffer from higher off-target activity or lower on-target editing efficiency than current adenine base editors (ABEs). To develop a CBE that retains the small size, low off-target activity and high on-target activity of current ABEs, we evolved the highly active deoxyadenosine deaminase TadA-8e to perform cytidine deamination using phage-assisted continuous evolution. Evolved TadA cytidine deaminases contain mutations at DNA-binding residues that alter enzyme selectivity to strongly favor deoxycytidine over deoxyadenosine deamination. Compared to commonly used CBEs, TadA-derived cytosine base editors (TadCBEs) offer similar or higher on-target activity, smaller size and substantially lower Cas-independent DNA and RNA off-target editing activity. We also identified a TadA dual base editor (TadDE) that performs equally efficient cytosine and adenine base editing. TadCBEs support single or multiplexed base editing at therapeutically relevant genomic loci in primary human T cells and primary human hematopoietic stem and progenitor cells. TadCBEs expand the utility of CBEs for precision gene editing.

DOI: https://doi.org/10.1038/s41587-022-01533-6
Sci Rep. 2022 Nov 09. 12(1): 19040

Porcine placental extract increase the cellular NAD levels in human epidermal keratinocytes.

Takeshi Katayoshi, Nobuaki Yamaura, Takahisa Nakajo, Natsuko Kitajima, Kentaro Tsuji-Naito.

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor for numerous enzymes involved in energy metabolism. Because decreasing NAD levels is a common hallmark of the aging process in various tissues and organs, maintaining NAD levels has recently been of interest for the prevention of aging and age-related diseases. Although placental extract (PE) are known to possess several anti-aging effects, the NAD-boosting activity of PE remains unknown. In this study, we found that porcine PE (PPE) significantly increased intracellular NAD levels in normal human epidermal keratinocytes (NHEKs). PPE also attenuated the NAD depletion induced by FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Interestingly, only the fraction containing nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and nicotinamide (NAM) restored NAD content in NHEKs in the absence of NAMPT activity. These results suggest that PPE increases intracellular NAD by providing NAD precursors such as NMN, NR, and NAM. Finally, we showed that the application of PPE to the stratum corneum of the reconstructed human epidermis significantly ameliorated FK866-induced NAD depletion, suggesting that topical PPE may be helpful for increasing skin NAD levels. This is the first study to report the novel biological activity of PE as an NAD booster in human epidermal cells.

DOI: https://doi.org/10.1038/s41598-022-23446-9
Biomedicines. 2022 Nov 10. pii: 2883. [Epub ahead of print]10(11):

Mitochondrial Transplantation Moderately Ameliorates Retinal Degeneration in Royal College of Surgeons Rats.

Shih-Fang Wu, Chih-Yao Lin, Rong-Kung Tsai, Yao-Tseng Wen, Feng-Huei Lin, Chia-Yu Chang, Ching-I Shen, Shinn-Zong Lin, Horng-Jyh Harn, Tzyy-Wen Chiou, Chin-San Liu, Yan-Ting Chen, Hong-Lin Su.

  Retinal pigmented epithelial (RPE) cells possess high mitochondria content for energy production, which is required for phagocytosis and vision cycle metabolism. The mitochondrial integrity in RPE cells helps the homeostasis of photoreceptor turnover and prevents retina aging and degeneration. Mitochondrial transplantation benefits the recovery of several acute inflammatory diseases, leading us to investigate the effects of mitochondrial transplantation on retina degeneration. Allogeneic mitochondria were isolated and delivered into the vitreous chamber in the Royal College of Surgeons (RCS) rats, which exhibit inherited and early-onset retina degeneration. The progress of retina degeneration was examined with optical coherence tomography (OCT) and visual evoked potential (VEP) to determine the retina thickness and integrity of afferent electrical signals from affected eyes, respectively. We found that mitochondria engraftment moderately attenuated the degeneration of retinal layers in RCS rats by histological examination. This result was consistent with the OCT measurement of retina thickness around the optic disc. The VEP analysis revealed that the peak one (N1) latency, representing the arriving time of electrical impulse from the retina to cortex, was substantially maintained as the normal value after the mitochondrial transplantation. This result suggests that the intra-vitreous transplanted mitochondria ameliorate the degeneration of photoreceptors in RCS rats and might be potential for clinical application.

Keywords:  macular degeneration; mitochondrial transplantation; retinal degeneration; retinitis pigmentosa

DOI:  https://doi.org/10.3390/biomedicines10112883
Cells. 2022 Oct 24. pii: 3351. [Epub ahead of print]11(21):

Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.

Domiziana Costamagna, Valérie Casters, Marc Beltrà, Maurilio Sampaolesi, Anja Van Campenhout, Els Ortibus, Kaat Desloovere, Robin Duelen.

  Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP.

Keywords:  hereditary spastic paraplegia; iPSC disease modeling; motor neuron differentiation; neuromuscular junction; skeletal muscle differentiation

DOI:  https://doi.org/10.3390/cells11213351