bims-mitmed 2022-07-24 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–07–24
28 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.
Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.
Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
Mitochondria and mitochondrial disorders: an overview update.
Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis.
Expanding the phenotype of DNAJC30-associated Leigh syndrome.
Mitochondrial Hepatopathy.
Cellular and mitochondrial quality control mechanisms in maintaining homeostasis in ageing.
From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy.
Midbrain on Fire: mtDNA Ignites Neuroinflammation in PRKN-P.
Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.
A new pathogenic POLG variant.
Alcohol, neuronal plasticity, and mitochondrial trafficking.
Structural overview of the translocase of the mitochondrial outer membrane complex.
Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia.
The accelerated evolution of human cytochrome c oxidase - Selection for reduced rate and proton pumping efficiency?
A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers?
Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate.
Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-eclampsia.
Mitochondrial genome undergoes de novo DNA methylation that protects mtDNA against oxidative damage during the peri-implantation window.
Transcription factor EB-mediated mesenchymal stem cell therapy induces autophagy and alleviates spinocerebellar ataxia type 3 defects in neuronal cells model.
Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.
Vitamin B3, nicotinamide, enhances mitochondrial metabolism to promote differentiation of the retinal pigment epithelium.
LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson's disease.
Sirt6 deficiency contributes to mitochondrial fission and oxidative damage in podocytes via ROCK1-Drp1 signalling pathway.
Targeting mitochondria in the regulation of neurodegenerative diseases: A comprehensive review.
Transcriptional profiles of genes related to mitochondrial aging in placental pathologies.
NRF2/PGC-1α-mediated mitochondrial biogenesis contributes to T-2 toxin-induced toxicity in human neuroblastoma SH-SY5Y cells.

EMBO J. 2022 Jul 20. e110784

AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.

Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klußmann, Ines Neundorf, David A Stroud, Michael T Ryan, Aleksandra Trifunovic, Ulrich Brandt, Jan Riemer.

  The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.

Keywords:  AIFM1; MIA40-CHCHD4; NDUFS5; complex I; mitochondrial disulfide relay

DOI:  https://doi.org/10.15252/embj.2022110784
Nature. 2022 Jul 20.

Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.

Aida Rodríguez-Nuevo, Ariadna Torres-Sanchez, Juan M Duran, Cristian De Guirior, Maria Angeles Martínez-Zamora, Elvan Böke.

Oocytes form before birth and remain viable for several decades before fertilization1. Although poor oocyte quality accounts for most female fertility problems, little is known about how oocytes maintain cellular fitness, or why their quality eventually declines with age2. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilization and embryo survival3-5. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced electron transport chain. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report a physiological cell type without complex I in animals. Our findings also clarify why patients with complex-I-related hereditary mitochondrial diseases do not experience subfertility. Complex I suppression represents an evolutionarily conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.

DOI: https://doi.org/10.1038/s41586-022-04979-5
Cell Rep. 2022 Jul 19. pii: S2211-1247(22)00930-5. [Epub ahead of print]40(3): 111124

Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.

Alberto Danese, Simone Patergnani, Alessandra Maresca, Camille Peron, Andrea Raimondi, Leonardo Caporali, Saverio Marchi, Chiara La Morgia, Valentina Del Dotto, Claudia Zanna, Angelo Iannielli, Alice Segnali, Ivano Di Meo, Andrea Cavaliere, Magdalena Lebiedzinska-Arciszewska, Mariusz R Wieckowski, Andrea Martinuzzi, Milton N Moraes-Filho, Solange R Salomao, Adriana Berezovsky, Rubens Belfort, Christopher Buser, Fred N Ross-Cisneros, Alfredo A Sadun, Carlo Tacchetti, Vania Broccoli, Carlotta Giorgi, Valeria Tiranti, Valerio Carelli, Paolo Pinton.

  Leber's hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.

Keywords:  CP: Neuroscience; LHON; autophagy; cybrids; iPSCs; mitochondria; mitophagy; mtDNA; optic nerve; retinal ganglion cells; therapy

DOI:  https://doi.org/10.1016/j.celrep.2022.111124
Endocr Regul. 2022 Jul 13. 56(3): 232-248

Mitochondria and mitochondrial disorders: an overview update.

Vibhuti Rambani, Dominika Hromnikova, Daniela Gasperikova, Martina Skopkova.

  Mitochondria, the cell powerhouse, are membrane-bound organelles present in the cytoplasm of almost all the eukaryotic cells. Their main function is to generate energy in the form of adenosine triphosphate (ATP). In addition, mitochondria store calcium for the cell signaling activities, generate heat, harbor pathways of intermediate metabolism and mediate cell growth and death. Primary mitochondrial diseases (MDs) form a clinically as well as genetically heterogeneous group of inherited disorders that result from the mitochondrial energetic metabolism malfunctions. The lifetime risk of the MDs development is estimated at 1:1470 of newborns, which makes them one of the most recurrent groups of inherited disorders with an important burden for society. MDs are progressive with wide range of symptoms of variable severity that can emerge congenitally or anytime during the life. MD can be caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA genes. Mutations inducing impairment of mitochondrial function have been found in more than 400 genes. Furthermore, more than 1200 nuclear genes, which could play a role in the MDs' genetic etiology, are involved in the mitochondrial activities. However, the knowledge regarding the mechanism of the mitochondrial pathogenicity appears to be most essential for the development of effective patient's treatment suffering from the mitochondrial disease. This is an overview update focused on the mitochondrial biology and the mitochondrial diseases associated genes.

Keywords:  genes; inherited disorder; mitochondria

DOI:  https://doi.org/10.2478/enr-2022-0025
AIDS. 2022 Jul 15.

Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis.

Matthew Hunt, Megan M Mcniff, Amy E Vincent, Caroline Sabin, Alan Winston, Brendan A I Payne.

OBJECTIVE: To quantify mitochondrial function in skeletal muscle of people treated with contemporary antiretroviral therapy.
DESIGN: Cross-sectional observational study.
METHODS: Quantitative multiplex immunofluorescence was performed to determine mitochondrial mass and respiratory chain complex abundance in individual myofibres from tibialis anterior biopsies. Individual myofibres were captured by laser microdissection and mitochondrial DNA (mtDNA) content and large-scale deletions were measured by real-time PCR.
RESULTS: Forty five antiretroviral therapy (ART) treated people with HIV (PWH, mean age 58 years, mean duration of ART 125 months) were compared with 15 HIV negative age-matched controls. Mitochondrial complex I (CI) deficiency was observed at higher proportional levels in PWH than negative controls (P = 0.008). Myofibre mitochondrial mass did not differ by HIV status.No ART class was significantly associated with mitochondrial deficiency, including prior exposure to historical NRTIs (nucleoside analogue reverse transcriptase inhibitors) associated with systemic mitochondrial toxicity.To exclude an effect of untreated HIV, we also studied skeletal muscle from 13 ART-naïve PWH (mean age 37). These showed negligible CI defects, as well as comparable myofibre mitochondrial mass to ART-treated PWH.Most CI-deficient myofibres contained mtDNA deletions. No mtDNA depletion was detected.
CONCLUSION: Here, we show that PWH treated with contemporary ART have mitochondrial dysfunction in skeletal muscle, exceeding that expected due to age alone. Surprisingly, this was not mediated by prior exposure to mitochondrially toxic NRTIs, suggesting novel mechanisms of mitochondrial dysfunction in contemporary ART-treated PWH. These findings are relevant for better understanding successful ageing in PWH.

DOI: https://doi.org/10.1097/QAD.0000000000003334
Clin Genet. 2022 Jul 21.

Expanding the phenotype of DNAJC30-associated Leigh syndrome.

Marta Zawadzka, Magdalena Krygier, Małgorzata Pawłowicz, Matheus Vernet Machado Bressan Wilke, Karolina Rutkowska, Naig Gueguen, Valerie Desquiret-Dumas, Eric W Klee, Lisa A Schimmenti, Jarosław Sławek, Vincent Procaccio, Rafał Płoski, Maria Mazurkiewicz-Bełdzińska.

  Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement. This article is protected by copyright. All rights reserved.

Keywords:  DNAJC30; Leigh syndrome; basal ganglia; dystonia; dystonic gait; mitochondrial disease; neurodegenerative disease; optic neuropathy; spasticity

DOI:  https://doi.org/10.1111/cge.14196
Clin Liver Dis. 2022 Aug;pii: S1089-3261(22)00020-4. [Epub ahead of print]26(3): 421-438

Mitochondrial Hepatopathy.

Mary Ayers, Simon P Horslen, Anna María Gómez, James E Squires.

  Mitochondrial hepatopathies are a subset of mitochondrial diseases defined by primary dysfunction of hepatocyte mitochondria leading to a phenotype of hepatocyte cell injury, steatosis, or liver failure. Increasingly, the diagnosis is established by new sequencing approaches that combine analysis of both nuclear DNA and mitochondrial DNA and allow for timely diagnosis in most patients. Despite advances in diagnostics, for most affected children their disorders are relentlessly progressive, and result in substantial morbidity and mortality. Treatment remains mainly supportive; however, novel therapeutics and a more definitive role for liver transplantation hold promise for affected children.

Keywords:  Acute liver failure; Children; Hepatocerebral dysfunction; Mitochondrial disease

DOI:  https://doi.org/10.1016/j.cld.2022.03.006
Rejuvenation Res. 2022 Jul 19.

Cellular and mitochondrial quality control mechanisms in maintaining homeostasis in ageing.

Urvashi Langeh, Vishal Kumar, Anoop Kumar, Pradeep Kumar, Charan Singh, Arti Singh.

Aging is a natural process in all living organisms defined as destruction of cell function as a result of long-term accumulation of damages. Autophagy is a cellular house safeguard pathway which responsible for degrading damaged cellular organelles. Moreover, it maintains cellular homeostasis, control lifetime, and longevity. Damaged mitochondrial accumulation is a characteristic of aging which associated with neurodegeneration. Mitochondria functions as a principal energy source via supplying ATP through oxidative phosphorylation which serves as fuel for neuronal function. Mitophagy and mitochondrial specific autophagy plays an important role in maintenance of neuronal health via the removal of dysfunctional and aged mitochondria. The mitochondrial QC system involves different strategies for protecting against mitochondrial dysfunction and maintaining healthy mitochondria in cells. Mitochondrial function protection could be a strategy for the promotion of neuroprotection. Mitophagy, could be an effective target for drug discovery. Therefore, further detailed studies for mechanism of mitophagy will advance our mitochondrial phenotype knowledge and understanding to disease pathogenesis. This review mainly focuses on ageing mediated mechanism of autophagy and mitophagy for maintaining the cellular homeostasis and longevity.

DOI: https://doi.org/10.1089/rej.2022.0027
Cold Spring Harb Perspect Med. 2022 Jul 21. pii: a041282. [Epub ahead of print]12(6):

From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy.

Benson S Chen, Patrick Yu-Wai-Man.

Leber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial disorder that presents with severe bilateral sequential vision loss, due to the selective degeneration of retinal ganglion cells (RGCs). Since the mitochondrial genetic basis for LHON was uncovered in 1988, considerable progress has been made in understanding the pathogenetic mechanisms driving RGC loss, which has enabled the development of therapeutic approaches aimed at mitigating the underlying mitochondrial dysfunction. In this review, we explore the genetics of LHON, from bench to bedside, focusing on the pathogenetic mechanisms and how these have informed the development of different gene therapy approaches, in particular the technique of allotopic expression with adeno-associated viral vectors. Finally, we provide an overview of the recent gene therapy clinical trials and consider the unanswered questions, challenges, and future prospects.

DOI: https://doi.org/10.1101/cshperspect.a041282
Mov Disord. 2022 Jul;37(7): 1332-1334

Midbrain on Fire: mtDNA Ignites Neuroinflammation in PRKN-P.

Derek P Narendra, Julia A Thayer.

DOI: https://doi.org/10.1002/mds.29073
Commun Biol. 2022 Jul 18. 5(1): 717

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.

Yingli Gu, Flora Guerra, Mingzheng Hu, Alexander Pope, Kijung Sung, Wanlin Yang, Simone Jetha, Thomas A Shoff, Tessanya Gunatilake, Owen Dahlkamp, Linda Zhixia Shi, Fiore Manganelli, Maria Nolano, Yue Zhou, Jianqing Ding, Cecilia Bucci, Chengbiao Wu.

Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7V162M mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic fibroblasts (MEFs). Primary cultured E18 dorsal root ganglion (DRG) sensory neurons also show mitochondrial fragmentation and altered axonal mitochondrial movement. In addition, we demonstrate that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalize the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study reveals, for the first time, that expression of CMT2B Rab7 mutation at the physiological level enhances Drp1 activity to promote mitochondrial fission, potentially underlying selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

DOI: https://doi.org/10.1038/s42003-022-03632-1
Mol Genet Metab Rep. 2022 Sep;32 100890

A new pathogenic POLG variant.

S Nicholas Russo, Ekta G Shah, William C Copeland, Mary Kay Koenig.

  POLG gene mutations are the most common causes of inherited mitochondrial disorders. The enzyme produced by this gene is responsible for the replication and repair of mitochondrial DNA. To date, around 300 pathogenic variants have been described in this gene. The resulting clinical outcomes of POLG mutations are widely variable in both phenotype and severity. There is considerable overlap in the phenotype of the so-called POLG syndromes with no clear genotype-phenotype correlation. Here we describe a newly discovered pathogenic variant in the POLG gene in a 7-year-old male that died of uncontrollable refractory status epilepticus. Genetic epilepsy panel sequencing identified two variants in the POLG gene, the common p.A467T pathological mutation and a novel p.S809R POLG variant found in trans with the p.A467T POLG that accompanied a severely reduced mitochondrial DNA level in the patient's tissues.

Keywords:  Alpers-Huttenlocher syndrome; DNA polymerase gamma; Mitochondria; Mitochondrial depletion; POLG syndrome

DOI:  https://doi.org/10.1016/j.ymgmr.2022.100890
Proc Natl Acad Sci U S A. 2022 Jul 19. 119(29): e2208744119

Alcohol, neuronal plasticity, and mitochondrial trafficking.

John Hernandez, Karla R Kaun.

DOI: https://doi.org/10.1073/pnas.2208744119
Biophys Physicobiol. 2022 ;19 e190022

Structural overview of the translocase of the mitochondrial outer membrane complex.

Yuhei Araiso, Toshiya Endo.

  Most mitochondrial proteins are synthesized as precursor proteins (preproteins) in the cytosol and imported into mitochondria. The translocator of the outer membrane (TOM) complex functions as a main entry gate for the import of mitochondrial proteins. The TOM complex is a multi-subunit membrane protein complex composed of a β-barrel channel Tom40 and six single-pass membrane proteins. Recent cryo-EM studies have revealed high-resolution structures of the yeast and human TOM complexes, which enabled us to discuss the mechanism of protein import at an amino-acid residue level. The cryo-EM structures show that two Tom40 β-barrels are surrounded by two sets of small Tom subunits to form a dimeric structure. The intermembrane space (IMS) domains of Tom40, Tom22, and Tom7 form a binding site for presequence-containing preproteins in the middle of the dimer to achieve their efficient transfer of to the downstream translocase, the TIM23 complex. The N-terminal segment of Tom40 spans the channel from the cytosol to the IMS to interact with Tom5 at the periphery of the dimer, where downstream components of presequence-lacking preproteins are recruited. Structure-based biochemical analyses together with crosslinking experiments revealed that each Tom40 channel possesses two distinct paths and exit sites for protein translocation of different sets of mitochondrial preproteins. Here we summarize the current knowledge on the structural features, protein translocation mechanisms, and remaining questions for the TOM complexes, with particular emphasis on their determined cryo-EM structures. This article is an extended version of the Japanese article, Structural basis for protein translocation by the translocase of the outer mitochondrial membrane, published in SEIBUTSU BUTSURI Vol. 60, p. 280-283 (2020).

Keywords:  Cryo-EM; TOM complex preprotein; mitochondria; protein translocation

DOI:  https://doi.org/10.2142/biophysico.bppb-v19.0022
J Lipid Res. 2022 Jul 15. pii: S0022-2275(22)00088-8. [Epub ahead of print] 100255

Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich's ataxia.

Dezhen Wang, Elaine S Ho, M Grazia Cotticelli, Peining Xu, Jill S Napierala, Lauren A Hauser, Marek Napierala, Blanca E Himes, Robert B Wilson, David R Lynch, Clementina Mesaros.

  Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a triplet guanine-adenine-adenine (GAA) repeat expansion in intron 1 of the FXN gene, which leads to decreased levels of the frataxin protein. Frataxin is involved in the formation of iron-sulfur (Fe-S) cluster prosthetic groups for various metabolic enzymes. To provide a better understanding of the metabolic status of FRDA patients, here we used patient-derived fibroblast cells as a surrogate tissue for metabolic and lipidomic profiling by liquid-chromatography high resolution-mass spectrometry (LC-HRMS). We found elevated HMG-CoA and β-hydroxybutyrate (BHB)-CoA levels, implying dysregulated fatty acid oxidation, which was further demonstrated by elevated acyl-carnitine levels. Lipidomic profiling identified dysregulated levels of several lipid classes in FRDA fibroblast cells when compared with non-FRDA fibroblast cells. For example, levels of several ceramides were significantly increased in FRDA fibroblast cells; these results positively correlated with the GAA repeat length and negatively correlated with the frataxin protein levels. Furthermore, stable isotope tracing experiments indicated increased ceramide synthesis, especially for long chain fatty acid-ceramides, in FRDA fibroblast cells compared to ceramide synthesis in healthy control fibroblast cells. In addition, PUFA containing triglycerides and phosphatidylglycerols were enriched in FRDA fibroblast cells and negatively correlated with frataxin levels, suggesting lipid remodeling as a result of FXN deficiency. Altogether, we demonstrate patient-derived fibroblast cells exhibited dysregulated metabolic capabilities, and their lipid dysfunction predicted the severity of FRDA, making them a useful surrogate to study the metabolic status in FRDA.

Keywords:  ceramides; fatty acids oxidation; frataxin; lipid remodeling; lipidomics; neurodegenerative disorders; phospholipids; stable isotope tracing; triglycerides; triplet repeat expansion

DOI:  https://doi.org/10.1016/j.jlr.2022.100255
Biochim Biophys Acta Bioenerg. 2022 Jul 15. pii: S0005-2728(22)00064-0. [Epub ahead of print] 148595

The accelerated evolution of human cytochrome c oxidase - Selection for reduced rate and proton pumping efficiency?

Hagai Rottenberg.

  The cytochrome c oxidase complex, complex VI (CIV), catalyzes the terminal step of the mitochondrial electron transport chain where the reduction of oxygen to water by cytochrome c is coupled to the generation of a protonmotive force that drive the synthesis of ATP. CIV evolution was greatly accelerated in humans and other anthropoid primates and appears to be driven by adaptive selection. However, it is not known if there are significant functional differences between the anthropoid primates CIV, and other mammals. Comparison of the high-resolution structures of bovine CIV, mouse CIV and human CIV shows structural differences that are associated with anthropoid-specific substitutions. Here I examine the possible effects of these substitutions in four CIV peptides that are known to affect proton pumping: the mtDNA-coded subunits I, II and III, and the nuclear-encoded subunit VIa2. I conclude that many of the anthropoid-specific substitutions could be expected to modulate the rate and/or the efficiency of proton pumping. These results are compatible with the previously proposed hypothesis that the accelerated evolution of CIV in anthropoid primates is driven by selection pressure to lower the mitochondrial protonmotive force and thus decrease the rate of superoxide generation by mitochondria.

Keywords:  Anthropoid primates; Cytochrome c oxidase; Human; Proton pumping; Protonmotive force

DOI:  https://doi.org/10.1016/j.bbabio.2022.148595
J Gen Physiol. 2022 Sep 05. pii: e202213167. [Epub ahead of print]154(9):

A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers?

Carlo Reggiani, Lorenzo Marcucci.

Mitochondria are characterized by a high capacity to accumulate calcium thanks to the electrochemical gradient created by the extrusion of protons in the respiratory chain. Thereby calcium can enter crossing the inner mitochondrial membrane via MCU complex, a high-capacity, low-affinity transport mechanism. Calcium uptake serves numerous purposes, among them the regulation of three dehydrogenases of the citric cycle, apoptosis via permeability transition, and, in some cell types, modulation of cytosolic calcium transients. This Review is focused on mitochondrial calcium uptake in skeletal muscle fibers and aims to reanalyze its functional impact. In particular, we ask whether mitochondrial calcium uptake is relevant for the control of cytosolic calcium transients and therefore of contractile performance. Recent data suggest that this may be the case, at least in particular conditions, as modified expression of MCU complex subunits or of proteins involved in mitochondrial dynamics and ablation of the main cytosolic calcium buffer, parvalbumin.

DOI: https://doi.org/10.1085/jgp.202213167
Front Cell Dev Biol. 2022 ;10 886393

Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate.

Kaya L Persad, Gary D Lopaschuk.

  Alterations in energy metabolism play a major role in the lineage of cardiomyocytes, such as the dramatic changes that occur in the transition from neonate to newborn. As cardiomyocytes mature, they shift from a primarily glycolytic state to a mitochondrial oxidative metabolic state. Metabolic intermediates and metabolites may have epigenetic and transcriptional roles in controlling cell fate by increasing mitochondrial biogenesis. In the maturing cardiomyocyte, such as in the postnatal heart, fatty acid oxidation increases in conjunction with increased mitochondrial biogenesis driven by the transcriptional coregulator PGC1-α. PGC1-α is necessary for mitochondrial biogenesis in the heart at birth, with deficiencies leading to postnatal cardiomyopathy. While stem cell therapy as a treatment for heart failure requires further investigation, studies suggest that adult stem cells may secrete cardioprotective factors which may regulate cardiomyocyte differentiation and survival. This review will discuss how metabolism influences mitochondrial biogenesis and how mitochondrial biogenesis influences cell fate, particularly in the context of the developing cardiomyocyte. The implications of energy metabolism on stem cell differentiation into cardiomyocytes and how this may be utilized as a therapy against heart failure and cardiovascular disease will also be discussed.

Keywords:  cardiomyocyte; cell fate; glycolysis mitochondrial contribution to cell maturation; metabolism; mitochondrial maturation; postnatal development

DOI:  https://doi.org/10.3389/fcell.2022.886393
Hum Hered. 2022 Jul 18.

Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-eclampsia.

Baohua Zhou, Xuelian Chu, Caijuan Zhang, Xiufeng Liang.

OBJECTIVES: Impairment of mitochondrial function caused by pathogenic mitochondrial DNA (mtDNA) mutations has been found to be associated with pre-eclampsia (PE). However, the underlying mechanism of PE remains poorly undetermined. The aim of this study is to evaluate the relationship between mitochondrial tRNAs (mt-tRNAs) variants and PE.
MATERIAL AND METHODS: The mt-tRNAs variants in a cohort of 100 pregnant women with PE and 100 healthy subjects were examined by PCR-Sager sequencing. Moreover, the phylogenetic conservation analysis, mitochondrial haplogroup analysis, as well as pathogenicity scoring system were used to assess the potential pathogenicity of these tRNA variants.
RESULTS: We identified five possible pathogenic mt-tRNA variants: tRNAPhe A608G, tRNAIle A4263G, tRNAAla T5587C, tRNALeu(CUN) G12294C and tRNAPro G15995A. We noticed that these variants were not detected in control subjects and occurred at the positions which were extremely conserved. Alternations in tRNAs structure caused by these variants may lead to the failures in tRNAs metabolism, which may subsequently may lead to the impairment of mitochondrial translation, as well as the respiratory chain functions. Thus, mt-tRNA variants may be involved in the pathogenesis of PE.
CONCLUSIONS: Taken together, our data indicated that variants in mt-tRNA genes were the important contributors to PE; screening for mt-tRNA variants was recommended for early detection and prevention of PE.

DOI: https://doi.org/10.1159/000525663
Proc Natl Acad Sci U S A. 2022 Jul 26. 119(30): e2201168119

Mitochondrial genome undergoes de novo DNA methylation that protects mtDNA against oxidative damage during the peri-implantation window.

Yuan Yue, Likun Ren, Chao Zhang, Kai Miao, Kun Tan, Qianying Yang, Yupei Hu, Guangyin Xi, Gang Luo, Mingyao Yang, Jingyu Zhang, Zhuocheng Hou, Lei An, Jianhui Tian.

  Mitochondrial remodeling during the peri-implantation stage is the hallmark event essential for normal embryogenesis. Among the changes, enhanced oxidative phosphorylation is critical for supporting high energy demands of postimplantation embryos, but increases mitochondrial oxidative stress, which in turn threatens mitochondrial DNA (mtDNA) stability. However, how mitochondria protect their own histone-lacking mtDNA, during this stage remains unclear. Concurrently, the mitochondrial genome gain DNA methylation by this stage. Its spatiotemporal coincidence with enhanced mitochondrial stress led us to ask if mtDNA methylation has a role in maintaining mitochondrial genome stability. Herein, we report that mitochondrial genome undergoes de novo mtDNA methylation that can protect mtDNA against enhanced oxidative damage during the peri-implantation window. Mitochondrial genome gains extensive mtDNA methylation during transition from blastocysts to postimplantation embryos, thus establishing relatively hypermethylated mtDNA from hypomethylated state in blastocysts. Mechanistic study revealed that DNA methyltransferase 3A (DNMT3A) and DNMT3B enter mitochondria during this process and bind to mtDNA, via their unique mitochondrial targeting sequences. Importantly, loss- and gain-of-function analyses indicated that DNMT3A and DNMT3B are responsible for catalyzing de novo mtDNA methylation, in a synergistic manner. Finally, we proved, in vivo and in vitro, that increased mtDNA methylation functions to protect mitochondrial genome against mtDNA damage induced by increased mitochondrial oxidative stress. Together, we reveal mtDNA methylation dynamics and its underlying mechanism during the critical developmental window. We also provide the functional link between mitochondrial epigenetic remodeling and metabolic changes, which reveals a role for nuclear-mitochondrial crosstalk in establishing mitoepigenetics and maintaining mitochondrial homeostasis.

Keywords:  DNMT3A/3B; de novo DNA methylation; mitochondrial DNA; mitochondrial oxidative damage; peri-implantation

DOI:  https://doi.org/10.1073/pnas.2201168119
Cell Death Dis. 2022 Jul 18. 13(7): 622

Transcription factor EB-mediated mesenchymal stem cell therapy induces autophagy and alleviates spinocerebellar ataxia type 3 defects in neuronal cells model.

Xiaobo Han, Jean de Dieu Habimana, Amy L Li, Rongqi Huang, Omar Mukama, Weiyue Deng, Ling Wang, Yuying Zhang, Wei Wang, Sihao Deng, Kexin Peng, Bing Ni, Shusheng Zhang, Jufang Huang, Xiao-Xin Yan, Zhiyuan Li.

Defects in ataxin-3 proteins and CAG repeat expansions in its coding gene ATXN3 cause Spinocerebellar Ataxia Type 3 (SCA3) or Machado-Joseph disease (MJD) polyglutamine neurodegenerative disease. The mutant proteins aggregate as inclusion bodies in cells and compete with wild-type ataxin-3, which leads to neuronal dysfunction or death and impairs Beclin1-mediated autophagy. It has been reported that Mesenchymal stem cells (MSCs) can reliably treat several neurodegenerative diseases. Herein, we used a Transcription Factor EB (TFEB) nuclear translocation-mediated MSCs co-culture approach to reconstitute autophagy and lysosomal biogenesis, and reduce SCA3-like behaviors in induced pluripotent stem cells (iPSCs)-derived neuron cells models. Our iPSCs model showed enhanced expression of autophagy proteins, attenuated the expression and toxic effects of mutant ataxin-3 on neurons, and alleviated the effects of ataxin-3 on autophagy. Therefore, MSCs are associated with autophagy-inducing therapy and compared to animal models, our MSCs co-culture could be used as a novel and potential therapeutic approach to study SCA3 disease and other neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41419-022-05085-0
EMBO Mol Med. 2022 Jul 21. e15855

Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.

Laura Sanchez-Burgos, Belén Navarro-González, Santiago García-Martín, Oleksandra Sirozh, Jorge Mota-Pino, Elena Fueyo-Marcos, Héctor Tejero, Marta Elena Antón, Matilde Murga, Fátima Al-Shahrour, Oscar Fernandez-Capetillo.

  FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase-dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7-deficient cells showed that all of them unexpectedly activate a GCN2-dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR-activating drugs.

Keywords:  FBXW7; GCN2; ISR; drug resistance; mitochondria

DOI:  https://doi.org/10.15252/emmm.202215855
J Biol Chem. 2022 Jul 19. pii: S0021-9258(22)00728-1. [Epub ahead of print] 102286

Vitamin B3, nicotinamide, enhances mitochondrial metabolism to promote differentiation of the retinal pigment epithelium.

Roni A Hazim, Antonio E Paniagua, Lisa Tang, Krista Yang, Kristen K O Kim, Linsey Stiles, Ajit S Divakaruni, David S Williams.

  In the mammalian retina, a metabolic ecosystem exists in which photoreceptors acquire glucose from the choriocapillaris with the help of the retinal pigment epithelium (RPE). While the photoreceptor cells are primarily glycolytic, exhibiting Warburg-like metabolism, the RPE is reliant on mitochondrial respiration. However, the ways in which mitochondrial metabolism affect RPE cellular functions are not clear. We first used the human RPE cell line, ARPE-19, to examine mitochondrial metabolism in the context of cellular differentiation. We show that nicotinamide induced rapid differentiation of ARPE-19 cells, which was reversed by removal of supplemental nicotinamide. During the nicotinamide-induced differentiation, we observed using quantitative PCR, western blotting, electron microscopy, and metabolic respiration and tracing assays that (1) mitochondrial gene and protein expression increased, (2) mitochondria became larger with more tightly-folded cristae, and (3) mitochondrial metabolism was enhanced. Additionally, we show primary cultures of human fetal RPE cells responded similarly in the presence of nicotinamide. Furthermore, disruption of mitochondrial oxidation of pyruvate attenuated the nicotinamide-induced differentiation of the RPE cells. Together, our results demonstrate a remarkable effect of nicotinamide on RPE metabolism. We also identify mitochondrial respiration as a key contributor to the differentiated state of the RPE, and thus to many of the RPE functions that are essential for retinal health and photoreception.

Keywords:  RPE; differentiation; mitochondria; nicotinamide; retina

DOI:  https://doi.org/10.1016/j.jbc.2022.102286
NPJ Parkinsons Dis. 2022 Jul 19. 8(1): 92

LRRK2 kinase activity regulates GCase level and enzymatic activity differently depending on cell type in Parkinson's disease.

Maria Kedariti, Emanuele Frattini, Pascale Baden, Susanna Cogo, Laura Civiero, Elena Ziviani, Gianluca Zilio, Federico Bertoli, Massimo Aureli, Alice Kaganovich, Mark R Cookson, Leonidas Stefanis, Matthew Surface, Michela Deleidi, Alessio Di Fonzo, Roy N Alcalay, Hardy Rideout, Elisa Greggio, Nicoletta Plotegher.

Leucine-rich repeat kinase 2 (LRRK2) is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways, and immune function. Mutations in LRRK2 cause autosomal-dominant forms of Parkinson's disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we performed a comprehensive analysis of GCase levels and activity in complementary LRRK2 models, including (i) LRRK2 G2019S knock in (GSKI) mice, (ii) peripheral blood mononuclear cell (PBMCs), plasma, and fibroblasts from PD patients carrying LRRK2 G2019S mutation, (iii) patient iPSCs-derived neurons; (iv) endogenous and overexpressed cell models. In some of these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. GCase protein level is reduced in GSKI brain tissues and in G2019S iPSCs-derived neurons, but increased in fibroblasts and PBMCs from patients, suggesting cell-type-specific effects. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase in a cell-type-specific manner, with important implications in the context of therapeutic application of LRRK2 inhibitors in GBA1-linked and idiopathic PD.

DOI: https://doi.org/10.1038/s41531-022-00354-3
Cell Prolif. 2022 Jul 17. e13296

Sirt6 deficiency contributes to mitochondrial fission and oxidative damage in podocytes via ROCK1-Drp1 signalling pathway.

Zhaowei Chen, Wei Liang, Jijia Hu, Zijing Zhu, Jun Feng, Yiqiong Ma, Qian Yang, Guohua Ding.

OBJECTIVES: Increasing evidence suggests that mitochondrial dysfunction is the key driver of angiotensin II (Ang II)-induced kidney injury. This study was designed to investigate whether Sirtuin 6 (Sirt6) could affect Ang II-induced mitochondrial damage and the potential mechanisms.
MATERIALS AND METHODS: Podocyte-specific Sirt6 knockout mice were infused with Ang II and cultured podocytes were stimulated with Ang II to evaluate the effects of Sirt6 on mitochondrial structure and function in podocytes. Immunofluorescence staining was used to detect protein expression and mitochondrial morphology in vitro. Electron microscopy was used to assess mitochondrial morphology in mice. Western blotting was used to quantify protein expression.
RESULTS: Mitochondrial fission and decreased Sirt6 expression were observed in podocytes from Ang II-infused mice. In Sirt6-deficient mice, Ang II infusion induced increased apoptosis and mitochondrial fragmentation in podocytes than that in Ang II-infused wild-type mice. In cultured human podocytes, Sirt6 knockdown exacerbated Ang II-induced mitochondrial fission, whereas Sirt6 overexpression ameliorated the Ang II-induced changes in the balance between mitochondrial fusion and fission. Functional studies revealed that Sirt6 deficiency exacerbated mitochondrial fission by promoting dynamin-related protein 1 (Drp1) phosphorylation. Furthermore, Sirt6 mediated Drp1 phosphorylation by promoting Rho-associated coiled coil-containing protein kinase 1 (ROCK1) expression.
CONCLUSION: Our study has identified Sirt6 as a vital factor that protects against Ang II-induced mitochondrial fission and apoptosis in podocytes via the ROCK1-Drp1 signalling pathway.

DOI: https://doi.org/10.1111/cpr.13296
J Neurosci Res. 2022 Jul 20.

Targeting mitochondria in the regulation of neurodegenerative diseases: A comprehensive review.

Shashank Kumar Maurya, Suchi Gupta, Amrita Bakshi, Harpreet Kaur, Arushi Jain, Sabyasachi Senapati, Meghraj Singh Baghel.

  Mitochondria are one of the essential cellular organelles. Apart from being considered as the powerhouse of the cell, mitochondria have been widely known to regulate redox reaction, inflammation, cell survival, cell death, metabolism, etc., and are implicated in the progression of numerous disease conditions including neurodegenerative diseases. Since brain is an energy-demanding organ, mitochondria and their functions are important for maintaining normal brain homeostasis. Alterations in mitochondrial gene expression, mutations, and epigenetic modification contribute to inflammation and neurodegeneration. Dysregulation of reactive oxygen species production by mitochondria and aggregation of proteins in neurons leads to alteration in mitochondria functions which further causes neuronal death and progression of neurodegeneration. Pharmacological studies have prioritized mitochondria as a possible drug target in the regulation of neurodegenerative diseases. Therefore, the present review article has been intended to provide a comprehensive understanding of mitochondrial role in the development and progression of neurodegenerative diseases mainly Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis followed by possible intervention and future treatment strategies to combat mitochondrial-mediated neurodegeneration.

Keywords:  CNS disease; brain; mitochondria; neurodegeneration; neuroinflammation; neurons

DOI:  https://doi.org/10.1002/jnr.25110
Mol Hum Reprod. 2022 Jul 22. pii: gaac026. [Epub ahead of print]

Transcriptional profiles of genes related to mitochondrial aging in placental pathologies.

Lucy A Bartho, Daniel R McKeating, Natalie J Hannan, Tu'uhevaha J Kaitu'u-Lino, Anthony V Perkins.

  As the placenta develops across gestation, the mitochondria and other organelles like the endoplasmic reticulum (ER) must continue to adapt to stressors such as oxidative stress. As pregnancy approaches term, these stressors may contribute to placental aging, including mitochondrial changes leading to cellular senescence. When these processes are exacerbated, pregnancy pathologies arise. This study aimed to identify correlations between genes related to mitochondria, ER and cellular senescence in placentae complicated by pregnancy complications. Placental samples from pregnancies classified as preterm, term, post-term, preterm with fetal growth restriction (FGR), preterm with preeclampsia (PE) and preterm with PE and FGR were used to measure gene expression of TOMM20, MFN1, TFAM, MFN2, PARK2, PINK1, EIF2AK3, TP53 and ERN1. MetaboAnalyst 5.0 was used to generate heatmaps, principal component analysis (PCA) plots, correlation graphs and receiver operating characteristic (ROC) analysis. This study found that genes related mitochondrial dynamics and aging undergo changes in placentae affected by pregnancy pathologies. The TOMM20/PARK2 ratio may be a promising marker to discriminate between healthy and unhealthy placental tissue. Future studies should explore circulating biomarkers of mitochondrial aging and dysfunction as indicators of placental health.

Keywords:  aging; endoplasmic reticulum; mitochondria; placenta; senescence

DOI:  https://doi.org/10.1093/molehr/gaac026
Toxicol Appl Pharmacol. 2022 Jul 13. pii: S0041-008X(22)00312-X. [Epub ahead of print] 116167

NRF2/PGC-1α-mediated mitochondrial biogenesis contributes to T-2 toxin-induced toxicity in human neuroblastoma SH-SY5Y cells.

Yue Pang, Li Zhang, Qiao Liu, Hui Peng, Jun He, Hong Jin, Xueting Su, Jun Zhao, Jiabin Guo.

  The T-2 toxin is a highly toxic trichothecene mycotoxin that would cause serious toxicity in humans and animals. Recent studies suggest that the central nervous system (CNS) is susceptible to T-2 toxin, which can easily cross the blood-brain barrier, accumulate in brain tissues, and cause neurotoxicity. The growing evidence indicates that oxidative damage and mitochondrial dysfunction play a critical role in T-2 toxin-induced neurotoxicity, but the mechanisms are still poorly understood. Our present study showed that T-2 toxin decreased cell viability and increased lactate dehydrogenase leakage in human neuroblastoma SH-SY5Y cells in a concentration- and time-dependent manner. T-2 toxin elicited prominent oxidative stress and mitochondrial dysfunction, as evidenced by the promotion of cellular reactive oxygen species generation, disruption of the mitochondrial membrane potential, depletion of glutathione and reduction of the cellular ATP content. T-2 toxin impaired mitochondrial biogenesis, including decreased mitochondrial DNA copy number and affected the nuclear factor erythroid 2 related factor 2 (NRF2) / peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) pathway by upregulating NRF2 mRNA and protein expression while inhibiting the expression of PGC-1α, nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). NRF2 knockdown was found to significantly exacerbate T-2 toxin-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction, as well as aggravate mitochondrial biogenesis impairment. NRF2 knockdown compromised T-2 toxin-induced upregulation of NRF2, but augmented the inhibition of PGC-1α, NRF1, and TFAM by T-2 toxin. Taken together, these findings suggest that T-2 toxin-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells, at least in part by, NRF2/PGC-1α pathway-mediated mitochondrial biogenesis.

Keywords:  Mitochondrial biogenesis; NRF2/PGC-1α; Neurotoxicity; Oxidative stress; T-2 toxin

DOI:  https://doi.org/10.1016/j.taap.2022.116167