bims-mitmed 2023-07-02 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–07–02
28 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.
Mitochondrial fitness sustains healthy muscle aging.
Fulminant Neonatal Liver Failure in MPV 17-Related Mitochondrial DNA Depletion Syndrome.
The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.
Translation termination in human mitochondria - substrate specificity of mitochondrial release factors.
Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.
5-Aminolevulinic acid bypasses mitochondrial complex I deficiency and corrects physiological dysfunctions in Drosophila.
Structural analysis of mitochondrial rRNA gene variants identified in patients with deafness.
Highly Specialized Mechanisms for Mitochondrial Transport in Neurons: From Intracellular Mobility to Intercellular Transfer of Mitochondria.
Neural stem cell metabolism revisited: a critical role for mitochondria.
Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
Effects of Parkin on the Mitochondrial Genome in the Heart and Brain of Mitochondrial Mutator Mice.
The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated.
Insulin-Degrading Enzyme Interacts with Mitochondrial Ribosomes and Respiratory Chain Proteins.
mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
Implications of MCU complex in metabolic diseases.
Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus 10398A>G.
Sarcopenic obesity: emerging mechanisms and therapeutic potential.
Decreased LONP1 expression contributes to DNA damage and meiotic defects in oocytes.
Mitochondria Quality Control and Male Fertility.
Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
Single-cell multiomic analyses sheds light on mitochondrial mutational selection.
Genomic newborn screening for rare diseases.
Epicatechin promotes oocyte quality in mice during repeated superovulation.
Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights.
Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies.
Epigenetic regulation of mitochondrial-endoplasmic reticulum dynamics in kidney diseases.
Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress.

Nat Metab. 2023 06;5(6): 955-967

Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.

Alessandro Bitto, Anthony S Grillo, Takashi K Ito, Ian B Stanaway, Bao M G Nguyen, Kejun Ying, Herman Tung, Kaleb Smith, Ngoc Tran, Gunnar Velikanje, Silvan R Urfer, Jessica M Snyder, Jacob Barton, Ayush Sharma, Ernst-Bernhard Kayser, Lu Wang, Daniel L Smith, J Will Thompson, Laura DuBois, William DePaolo, Matt Kaeberlein.

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.

DOI: https://doi.org/10.1038/s42255-023-00815-w
Aging (Albany NY). 2023 Jun 24. 15

Mitochondrial fitness sustains healthy muscle aging.

Andrea Irazoki, Antonio Zorzano, David Sebastián.



Keywords:  aging; mitochondria; mitochondrial dynamics; mitophagy; sarcopenia

DOI:  https://doi.org/10.18632/aging.204857
Case Reports Hepatol. 2023 ;2023 4514552

Fulminant Neonatal Liver Failure in MPV 17-Related Mitochondrial DNA Depletion Syndrome.

Razan Abduljalil, Hadhami Ben Turkia, Aysha Fakhroo, Cristina Skrypnyk.

Mitochondrial depletion syndromes are well established causes of liver failure in infants. Hepatocerebral variant related to MPV17 gene defect is characterized by infantile onset of progressive liver failure, developmental delay, neurological manifestations, lactic acidosis, hypoglycemia, and mtDNA depletion in liver tissue. We report a hepatocerebral variant of mitochondrial DNA depletion syndrome in a neonate who presented with septic shock picture, hypoglycemia, jaundice, hypotonia, and rotatory nystagmus. Family history was significant for consanguinity and a brother who died at the age of 4 months. Investigations showed mild liver function derangement contrasting with severe coagulopathy, hyperlactatemia, and generalized aminoaciduria. The brain MRI was normal. Next generation sequencing (NGS) panel identified a MPV17 gene missense homozygous pathogenic variant. The infant expired at the age of 2 weeks with refractory ascites. This case illustrates a challenging diagnosis causing liver failure and death in neonatal period. Genetic testing of mitochondrial DNA depletion syndromes should be a part of liver failure workup in addition to other treatable disorders presenting with encephalo-hepatopathy in infancy.

DOI: https://doi.org/10.1155/2023/4514552
Mol Biol Cell. 2023 Jun 28. mbcE23050205

The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins.

Katharina Knöringer, Carina Groh, Lena Krämer, Kevin C Stein, Katja G Hansen, Jannik Zimmermann, Bruce Morgan, Johannes M Herrmann, Judith Frydman, Felix Boos.

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of non-imported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPRER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The level of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPRER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.

DOI: https://doi.org/10.1091/mbc.E23-05-0205
Biol Chem. 2023 Jun 29.

Translation termination in human mitochondria - substrate specificity of mitochondrial release factors.

Franziska Nadler, Ricarda Richter-Dennerlein.

  Mitochondria are the essential players in eukaryotic ATP production by oxidative phosphorylation, which relies on the maintenance and accurate expression of the mitochondrial genome. Even though the basic principles of translation are conserved due to the descendance from a bacterial ancestor, some deviations regarding translation factors as well as mRNA characteristics and the applied genetic code are present in human mitochondria. Together, these features are certain challenges during translation the mitochondrion has to handle. Here, we discuss the current knowledge regarding mitochondrial translation focusing on the termination process and the associated quality control mechanisms. We describe how mtRF1a resembles bacterial RF1 mechanistically and summarize in vitro and recent in vivo data leading to the conclusion of mtRF1a being the major mitochondrial release factor. On the other hand, we discuss the ongoing debate about the function of the second codon-dependent mitochondrial release factor mtRF1 regarding its role as a specialized termination factor. Finally, we link defects in mitochondrial translation termination to the activation of mitochondrial rescue mechanisms highlighting the importance of ribosome-associated quality control for sufficient respiratory function and therefore for human health.

Keywords:  COX1 translation; mitoribosome rescue; mitoribosome-associated quality control; mtRF1; mtRF1a; non-canonical stop codons

DOI:  https://doi.org/10.1515/hsz-2023-0127
Front Genet. 2023 ;14 1191159

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.

Asuman Gedikbasi, Guven Toksoy, Meryem Karaca, Cagri Gulec, Mehmet Cihan Balci, Dilek Gunes, Seda Gunes, Ayca Dilruba Aslanger, Gokcen Unverengil, Birsen Karaman, Seher Basaran, Mubeccel Demirkol, Gulden Fatma Gokcay, Zehra Oya Uyguner.

  Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

Keywords:  bi-genomic sequencing; differential diagnosis; exome sequencing; mitochondrial diseases; mtDNA

DOI:  https://doi.org/10.3389/fgene.2023.1191159
Hum Mol Genet. 2023 Jun 26. pii: ddad092. [Epub ahead of print]

5-Aminolevulinic acid bypasses mitochondrial complex I deficiency and corrects physiological dysfunctions in Drosophila.

Naoko Nozawa, Marie Noguchi, Kanako Shinno, Taro Saito, Akiko Asada, Takuya Ishii, Kiwamu Takahashi, Masahiro Ishizuka, Kanae Ando.

Complex I (CI) deficiency in mitochondrial oxidative phosphorylation (OXPHOS) is the most common cause of mitochondrial diseases, and limited evidence-based treatment options exist. While CI provides the most electrons to OXPHOS, complex II (CII) is another entry point of electrons. Enhancement of this pathway may compensate for a loss of CI; however, the effects of boosting CII activity on CI deficiency are unclear at the animal level. 5-Aminolevulinic acid (5-ALA) is a crucial precursor of heme, which is essential for CII, complex III, complex IV (CIV), and cytochrome c activities. Here, we show that feeding a combination of 5-ALA hydrochloride and sodium ferrous citrate (5-ALA-HCl + SFC) increases ATP production and suppresses defective phenotypes in Drosophila with CI deficiency. Knockdown of sicily, a Drosophila homolog of the critical CI assembly protein NDUFAF6, caused CI deficiency, accumulation of lactate and pyruvate, and detrimental phenotypes such as abnormal neuromuscular junction development, locomotor dysfunctions, and premature death. 5-ALA-HCl + SFC feeding increased ATP levels without recovery of CI activity. The activities of CII and CIV were upregulated, and accumulation of lactate and pyruvate was suppressed. 5-ALA-HCl + SFC feeding improved neuromuscular junction development and locomotor functions in sicily-knockdown flies. These results suggest that 5-ALA-HCl + SFC shifts metabolic programs to cope with CI deficiency.

DOI: https://doi.org/10.1093/hmg/ddad092
Front Physiol. 2023 ;14 1163496

Structural analysis of mitochondrial rRNA gene variants identified in patients with deafness.

Antón Vila-Sanjurjo, Natalia Mallo, Joanna L Elson, Paul M Smith, Emma L Blakely, Robert W Taylor.

  The last few years have witnessed dramatic advances in our understanding of the structure and function of the mammalian mito-ribosome. At the same time, the first attempts to elucidate the effects of mito-ribosomal fidelity (decoding accuracy) in disease have been made. Hence, the time is right to push an important frontier in our understanding of mitochondrial genetics, that is, the elucidation of the phenotypic effects of mtDNA variants affecting the functioning of the mito-ribosome. Here, we have assessed the structural and functional role of 93 mitochondrial (mt-) rRNA variants thought to be associated with deafness, including those located at non-conserved positions. Our analysis has used the structural description of the human mito-ribosome of the highest quality currently available, together with a new understanding of the phenotypic manifestation of mito-ribosomal-associated variants. Basically, any base change capable of inducing a fidelity phenotype may be considered non-silent. Under this light, out of 92 previously reported mt-rRNA variants thought to be associated with deafness, we found that 49 were potentially non-silent. We also dismissed a large number of reportedly pathogenic mtDNA variants, 41, as polymorphisms. These results drastically update our view on the implication of the primary sequence of mt-rRNA in the etiology of deafness and mitochondrial disease in general. Our data sheds much-needed light on the question of how mt-rRNA variants located at non-conserved positions may lead to mitochondrial disease and, most notably, provide evidence of the effect of haplotype context in the manifestation of some mt-rRNA variants.

Keywords:  deafness (hearing loss); haplotype; mito-ribosomal fidelity; mito-ribosome; mitochondrial rRNA mutations; mtDNA; mtDNA diseases

DOI:  https://doi.org/10.3389/fphys.2023.1163496
Biomolecules. 2023 06 03. pii: 938. [Epub ahead of print]13(6):

Highly Specialized Mechanisms for Mitochondrial Transport in Neurons: From Intracellular Mobility to Intercellular Transfer of Mitochondria.

Marta Zaninello, Camilla Bean.

  The highly specialized structure and function of neurons depend on a sophisticated organization of the cytoskeleton, which supports a similarly sophisticated system to traffic organelles and cargo vesicles. Mitochondria sustain crucial functions by providing energy and buffering calcium where it is needed. Accordingly, the distribution of mitochondria is not even in neurons and is regulated by a dynamic balance between active transport and stable docking events. This system is finely tuned to respond to changes in environmental conditions and neuronal activity. In this review, we summarize the mechanisms by which mitochondria are selectively transported in different compartments, taking into account the structure of the cytoskeleton, the molecular motors and the metabolism of neurons. Remarkably, the motor proteins driving the mitochondrial transport in axons have been shown to also mediate their transfer between cells. This so-named intercellular transport of mitochondria is opening new exciting perspectives in the treatment of multiple diseases.

Keywords:  TNTs; cytoskeleton; microtubules; mitochondria; mitochondrial transplantation; neuron; transport

DOI:  https://doi.org/10.3390/biom13060938
Trends Endocrinol Metab. 2023 Jun 26. pii: S1043-2760(23)00110-8. [Epub ahead of print]

Neural stem cell metabolism revisited: a critical role for mitochondria.

Valentina Scandella, Francesco Petrelli, Darcie L Moore, Simon M G Braun, Marlen Knobloch.

  Metabolism has emerged as a key regulator of stem cell behavior. Mitochondria are crucial metabolic organelles that are important for differentiated cells, yet considered less so for stem cells. However, recent studies have shown that mitochondria influence stem cell maintenance and fate decisions, inviting a revised look at this topic. In this review, we cover the current literature addressing the role of mitochondrial metabolism in mouse and human neural stem cells (NSCs) in the embryonic and adult brain. We summarize how mitochondria are implicated in fate regulation and how substrate oxidation affects NSC quiescence. We further explore single-cell RNA sequencing (scRNA-seq) data for metabolic signatures of adult NSCs, highlight emerging technologies reporting on metabolic signatures, and discuss mitochondrial metabolism in other stem cells.

Keywords:  metabolism; mitochondria; neural stem cells; quiescence

DOI:  https://doi.org/10.1016/j.tem.2023.05.008
Nat Genet. 2023 Jun 29.

Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.

Caleb A Lareau, Sonia M Dubois, Frank A Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D Praktiknjo, Patrick Maschmeyer, Jeffrey M Verboon, Jacob C Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni P Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Santosha A Vardhana, Ansuman T Satpathy, Aviv Regev, Vijay G Sankaran, Suneet Agarwal, Leif S Ludwig.

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.

DOI: https://doi.org/10.1038/s41588-023-01433-8
Adv Biol (Weinh). 2023 Jun 27. e2300154

Effects of Parkin on the Mitochondrial Genome in the Heart and Brain of Mitochondrial Mutator Mice.

Eliezer Z Lichter, Andrew J Trease, Kathryn Cooper, Kelly L Stauch, Howard S Fox.

  Mitochondrial dysfunction has been implicated in neurodegenerative diseases like Parkinson's disease (PD). This study investigates the role of Parkin, a protein involved in mitochondrial quality control, and strongly linked to PD, in the context of mitochondrial DNA (mtDNA) mutations. The authors use mitochondrial mutator mice (PolgD257A/D257A ) (Polg), which are bred with Parkin knockout (PKO) mice or mice with disinhibited Parkin (W402A). In the brain, mtDNA mutations are analyzed in synaptosomes, presynaptic neuronal terminals, which are far from neuronal soma, which likely renders mitochondria there more vulnerable compared with brain homogenate. Surprisingly, PKO results in reduced mtDNA mutations in the brain but increased control region multimer (CRMS) load in synaptosomes. In the heart, both PKO and W402A lead to increased mutations, with W402A showing more mutations in the heart than PKO. Computational analysis reveals many of these mutations are deleterious. These findings suggest that Parkin plays a tissue-dependent role in regulating mtDNA damage response, with differential effects in the brain and heart. Understanding the specific role of Parkin in different tissues may provide insights into the underlying mechanisms of PD and potential therapeutic strategies. Further investigation into these pathways can enhance the understanding of neurodegenerative diseases associated with mitochondrial dysfunction.

Keywords:  Parkinson's disease; mitochondrial dysfunction; mitochondrial genome; mtDNA; parkin

DOI:  https://doi.org/10.1002/adbi.202300154
Int J Mol Sci. 2023 Jun 14. pii: 10113. [Epub ahead of print]24(12):

The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated.

Yun-Seok Kim, Han A Reum Lee, Min Ji Lee, Ye Jin Park, Sehwan Mun, Chang June Yune, Tae Nyoung Chung, Jinkun Bae, Mi Jin Kim, Yong-Soo Choi, Kyuseok Kim.

  Previously, we have shown that mitochondrial transplantation in the sepsis model has immune modulatory effects. The mitochondrial function could have different characteristics dependent on cell types. Here, we investigated whether the effects of mitochondrial transplantation on the sepsis model could be different depending on the cell type, from which mitochondria were isolated. We isolated mitochondria from L6 muscle cells, clone 9 liver cells and mesenchymal stem cells (MSC). We tested the effects of mitochondrial transplantation using in vitro and in vivo sepsis models. We used the LPS stimulation of THP-1 cell, a monocyte cell line, as an in vitro model. First, we observed changes in mitochondrial function in the mitochondria-transplanted cells. Second, we compared the anti-inflammatory effects of mitochondrial transplantation. Third, we investigated the immune-enhancing effects using the endotoxin tolerance model. In the in vivo polymicrobial fecal slurry sepsis model, we examined the survival and biochemical effects of each type of mitochondrial transplantation. In the in vitro LPS model, mitochondrial transplantation with each cell type improved mitochondrial function, as measured by oxygen consumption. Among the three cell types, L6-mitochondrial transplantation significantly enhanced mitochondrial function. Mitochondrial transplantation with each cell type reduced hyper-inflammation in the acute phase of in vitro LPS model. It also enhanced immune function during the late immune suppression phase, as shown by endotoxin tolerance. These functions were not significantly different between the three cell types of origin for mitochondrial transplantation. However, only L6-mitochondrial transplantation significantly improved survival compared to the control in the polymicrobial intraabdominal sepsis model. The effects of mitochondria transplantation on both in vitro and in vivo sepsis models differed depending on the cell types of origin for mitochondria. L6-mitochondrial transplantation might be more beneficial in the sepsis model.

Keywords:  hyperinflammation; immune modulation; immune paralysis; mitochondria dysfunction; mitochondria transplantation; sepsis

DOI:  https://doi.org/10.3390/ijms241210113
Biomolecules. 2023 05 26. pii: 890. [Epub ahead of print]13(6):

Insulin-Degrading Enzyme Interacts with Mitochondrial Ribosomes and Respiratory Chain Proteins.

Ayse Yilmaz, Chiara Guerrera, Emmanuelle Waeckel-Énée, Joanna Lipecka, Barbara Bertocci, Peter van Endert.

  Insulin-degrading enzyme (IDE) is a highly conserved metalloprotease that is mainly localized in the cytosol. Although IDE can degrade insulin and some other low molecular weight substrates efficiently, its ubiquitous expression suggests additional functions supported by experimental findings, such as a role in stress responses and cellular protein homeostasis. The translation of a long full-length IDE transcript has been reported to result in targeting to mitochondria, but the role of IDE in this compartment is unknown. To obtain initial leads on the function of IDE in mitochondria, we used a proximity biotinylation approach to identify proteins interacting with wild-type and protease-dead IDE targeted to the mitochondrial matrix. We find that IDE interacts with multiple mitochondrial ribosomal proteins as well as with proteins involved in the synthesis and assembly of mitochondrial complex I and IV. The mitochondrial interactomes of wild type and mutant IDE are highly similar and do not reveal any likely proteolytic IDE substrates. We speculate that IDE could adopt similar additional non-proteolytic functions in mitochondria as in the cytosol, acting as a chaperone and contributing to protein homeostasis and stress responses.

Keywords:  chaperone; mitochondrial translation; mitochondrion; respiratory chain

DOI:  https://doi.org/10.3390/biom13060890
Nat Cell Biol. 2023 Jun 29.

mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.

Nuria Martinez-Lopez, Pamela Mattar, Miriam Toledo, Henrietta Bains, Manu Kalyani, Marie Louise Aoun, Mridul Sharma, Laura Beth J McIntire, Leslie Gunther-Cummins, Frank P Macaluso, Jennifer T Aguilan, Simone Sidoli, Mathieu Bourdenx, Rajat Singh.

Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.

DOI: https://doi.org/10.1038/s41556-023-01163-3
FASEB J. 2023 Aug;37(8): e23046

Implications of MCU complex in metabolic diseases.

Chen Li, Jiyu Sun, Xidan Zhang, Min Zhou, Xueqi Gan.

  Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more effective and convenient potent drugs are still being explored. Ca2+ across the inner mitochondrial membrane is a vital intracellular messenger that regulates energy metabolism and cellular Ca2+ homeostasis and is involved in cell death. Mitochondria rely on a selective mitochondrial Ca2+ unidirectional transport complex (MCU complex) in their inner membrane for Ca2+ uptake. We found that the channel contains several subunits and undergoes dramatic transformations in various pathological processes, especially in metabolic diseases. In this way, we believe that the MCU complex becomes a target with significant potential for these diseases. However, there is no review linking the two factors, thus hindering the possibility of new drug production. Here, we highlight the connection between MCU complex-related Ca2+ transport and the pathophysiology of metabolic diseases, adding understanding and insight at the molecular level to provide new insights for targeting MCU to reverse metabolism-related diseases.

Keywords:  MCU complex; homeostasis; metabolic disease; mitochondrial; structure

DOI:  https://doi.org/10.1096/fj.202300218R
Sci Rep. 2023 06 27. 13(1): 10405

Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus 10398A>G.

Molly Smullen, Meagan N Olson, Liam F Murray, Madhusoodhanan Suresh, Guang Yan, Pepper Dawes, Nathaniel J Barton, Jivanna N Mason, Yucheng Zhang, Aria A Fernandez-Fontaine, George M Church, Diego Mastroeni, Qi Wang, Elaine T Lim, Yingleong Chan, Benjamin Readhead.

Mitochondrial (MT) dysfunction has been associated with several neurodegenerative diseases including Alzheimer's disease (AD). While MT-copy number differences have been implicated in AD, the effect of MT heteroplasmy on AD has not been well characterized. Here, we analyzed over 1800 whole genome sequencing data from four AD cohorts in seven different tissue types to determine the extent of MT heteroplasmy present. While MT heteroplasmy was present throughout the entire MT genome for blood samples, we detected MT heteroplasmy only within the MT control region for brain samples. We observed that an MT variant 10398A>G (rs2853826) was significantly associated with overall MT heteroplasmy in brain tissue while also being linked with the largest number of distinct disease phenotypes of all annotated MT variants in MitoMap. Using gene-expression data from our brain samples, our modeling discovered several gene networks involved in mitochondrial respiratory chain and Complex I function associated with 10398A>G. The variant was also found to be an expression quantitative trait loci (eQTL) for the gene MT-ND3. We further characterized the effect of 10398A>G by phenotyping a population of lymphoblastoid cell-lines (LCLs) with and without the variant allele. Examination of RNA sequence data from these LCLs reveal that 10398A>G was an eQTL for MT-ND4. We also observed in LCLs that 10398A>G was significantly associated with overall MT heteroplasmy within the MT control region, confirming the initial findings observed in post-mortem brain tissue. These results provide novel evidence linking MT SNPs with MT heteroplasmy and open novel avenues for the investigation of pathomechanisms that are driven by this pleiotropic disease associated loci.

DOI: https://doi.org/10.1038/s41598-023-37541-y
Metabolism. 2023 Jun 26. pii: S0026-0495(23)00243-3. [Epub ahead of print] 155639

Sarcopenic obesity: emerging mechanisms and therapeutic potential.

Christopher L Axelrod, Wagner S Dantas, John P Kirwan.

  Sarcopenic obesity, or the loss of muscle mass and function associated with excess adiposity, is a largely untreatable medical condition associated with diminished quality of life and increased risk of mortality. To date, it remains somewhat paradoxical and mechanistically undefined as to why a subset of adults with obesity develop muscular decline, an anabolic stimulus generally associated with retention of lean mass. Here, we review evidence surrounding the definition, etiology, and treatment of sarcopenic obesity with an emphasis on emerging regulatory nodes with therapeutic potential. We review the available clinical evidence largely focused on diet, lifestyle, and behavioral interventions to improve quality of life in patients with sarcopenic obesity. Based upon available evidence, relieving consequences of energy burden such as oxidative stress, myosteatosis, and/or mitochondrial dysfunction is a promising area for therapeutic development in the treatment and management of sarcopenic obesity.

Keywords:  Aging; Mitochondrial quality control; Muscle function; Muscle mass; Obesity; Sarcopenia; Sarcopenic obesity

DOI:  https://doi.org/10.1016/j.metabol.2023.155639
Mol Reprod Dev. 2023 Jul 01.

Decreased LONP1 expression contributes to DNA damage and meiotic defects in oocytes.

Chuanming Liu, Manlin Xu, Yajie Guan, Lilin Li, Wenwen Liu, Bichun Guo, Xiaoqiang Sheng, Yang Zhang, Jidong Zhou, Xin Zhen, Guijun Yan, Haixiang Sun, Lijun Ding.

  Meiotic defects in oocytes are the primary reason for decreased female fertility with advanced maternal age. In this study, we revealed that decreased expression of ATP-dependent Lon peptidase 1 (LONP1) in aged oocytes and oocyte-specific depletion of LONP1 disrupt oocyte meiotic progression accompanying with mitochondrial dysfunction. In addition, LONP1 downregulation increased oocyte DNA damage. Moreover, we demonstrated that splicing factor proline and glutamine rich directly interacts with LONP1 and mediate the effect of LONP1 depletion on meiotic progression in oocytes. In summary, our data suggest that decreased expression of LONP1 is involved in advanced maternal age-related meiosis defects and that LONP1 represents a new therapeutic target to improve aged oocyte quality.

Keywords:  LONP1; SFPQ; meiotic defect; mitochondrial dysfunction; oocyte aging

DOI:  https://doi.org/10.1002/mrd.23694
Biology (Basel). 2023 Jun 06. pii: 827. [Epub ahead of print]12(6):

Mitochondria Quality Control and Male Fertility.

José Costa, Patrícia C Braga, Irene Rebelo, Pedro F Oliveira, Marco G Alves.

  Mitochondria are pivotal to cellular homeostasis, performing vital functions such as bioenergetics, biosynthesis, and cell signalling. Proper maintenance of these processes is crucial to prevent disease development and ensure optimal cell function. Mitochondrial dynamics, including fission, fusion, biogenesis, mitophagy, and apoptosis, maintain mitochondrial quality control, which is essential for overall cell health. In male reproduction, mitochondria play a pivotal role in germ cell development and any defects in mitochondrial quality can have serious consequences on male fertility. Reactive oxygen species (ROS) also play a crucial role in sperm capacitation, but excessive ROS levels can trigger oxidative damage. Any imbalance between ROS and sperm quality control, caused by non-communicable diseases or environmental factors, can lead to an increase in oxidative stress, cell damage, and apoptosis, which in turn affect sperm concentration, quality, and motility. Therefore, assessing mitochondrial functionality and quality control is essential to gain valuable insights into male infertility. In sum, proper mitochondrial functionality is essential for overall health, and particularly important for male fertility. The assessment of mitochondrial functionality and quality control can provide crucial information for the study and management of male infertility and may lead to the development of new strategies for its management.

Keywords:  male fertility; mitochondrial quality control; non-communicable diseases; spermatozoa

DOI:  https://doi.org/10.3390/biology12060827
Science. 2023 Jun 30. 380(6652): 1372-1380

Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.

Tao Zhang, Daichao Xu, Elijah Trefts, Mingming Lv, Hiroyuki Inuzuka, Guobin Song, Min Liu, Jianlin Lu, Jianping Liu, Chen Chu, Min Wang, Huibing Wang, Huyan Meng, Hui Liu, Yuan Zhuang, Xingxing Xie, Fabin Dang, Dongxian Guan, Yuqin Men, Shuwen Jiang, Cong Jiang, Xiaoming Dai, Jing Liu, Zhen Wang, Peiqiang Yan, Jingchao Wang, Zhenbo Tu, Mrigya Babuta, Emily Erickson, Alissandra L Hillis, Christian C Dibble, John M Asara, Gyongy Szabo, Piotr Sicinski, Ji Miao, Yu-Ru Lee, Lifeng Pan, Reuben J Shaw, Junying Yuan, Wenyi Wei.

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

DOI: https://doi.org/10.1126/science.abn1725
Nat Genet. 2023 Jun 29.

Single-cell multiomic analyses sheds light on mitochondrial mutational selection.

Sarah J Pickett, Gavin Hudson, Laura C Greaves.

DOI: https://doi.org/10.1038/s41588-023-01436-5
Nat Rev Genet. 2023 Jun 29.

Genomic newborn screening for rare diseases.

Zornitza Stark, Richard H Scott.

Rare diseases are a leading cause of infant mortality and lifelong disability. To improve outcomes, timely diagnosis and effective treatments are needed. Genomic sequencing has transformed the traditional diagnostic process, providing rapid, accurate and cost-effective genetic diagnoses to many. Incorporating genomic sequencing into newborn screening programmes at the population scale holds the promise of substantially expanding the early detection of treatable rare diseases, with stored genomic data potentially benefitting health over a lifetime and supporting further research. As several large-scale newborn genomic screening projects launch internationally, we review the challenges and opportunities presented, particularly the need to generate evidence of benefit and to address the ethical, legal and psychosocial issues that genomic newborn screening raises.

DOI: https://doi.org/10.1038/s41576-023-00621-w
Theriogenology. 2023 Jun 16. pii: S0093-691X(23)00233-9. [Epub ahead of print]209 40-49

Epicatechin promotes oocyte quality in mice during repeated superovulation.

Yun Feng, Zhulian Wu, Xin Zhao, Mosinan Chen, Sijia Li, Canqiang Lu, Deshun Shi, Fenghua Lu.

  The negative impacts of repeated superovulation on mitochondrial function and oocyte quality remain unresolved. Epicatechin (EC), a polyphenolic compound found in the human diet with strong antioxidant activity, was investigated for its effects and underlying mechanism on embryonic development after repeated superovulation. The results showed that as the number of superovulation cycles increased, the number of 2-cell embryos decreased, the development of embryos in subsequent in vitro culture was delayed, the apoptosis rate of blastocyst cells increased and the number of blastocyst cells decreased. However, intraperitoneal injection of EC (10 mg/kg body-weight) for two consecutive days during repeated superovulation increased mitochondrial DNA copies in 2-cell embryos of mice. It also promoted the expression of antioxidant enzyme genes in ovaries, increased the content of glutathione (GSH) content and improved the antioxidant capacity of ovaries. Altogether, these results revealed that intraperitoneal injection of EC could increase the embryonic mitochondrial DNA copy number (mtDNA-CN) and enhance the ovary's antioxidant capacity and GSH content, ultimately promoting the quality of mouse embryos in the process of repeated superovulation.

Keywords:  Epicatechin (EC); Mitochondrial DNA; Oocyte; Repeated superovulation

DOI:  https://doi.org/10.1016/j.theriogenology.2023.06.025
Cells. 2023 06 16. pii: 1646. [Epub ahead of print]12(12):

Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights.

P Hemachandra Reddy, Sudhir Kshirsagar, Chhanda Bose, Jangampalli Adi Pradeepkiran, Ashly Hindle, Sharda P Singh, Arubala P Reddy, Javaria Baig.

  RalBP1 (Rlip) is a stress-activated protein that is believed to play a large role in aging and neurodegenerative diseases such as Alzheimer's disease (AD) and other tauopathies. The purpose of our study was to understand the role of Rlip in mutant Tau-expressed immortalized hippocampal HT22 cells. In the current study, we used mutant Tau (mTau)-expressed HT22 neurons and HT22 cells transfected with Rlip-cDNA and/or silenced RNA, and studied the cell survival, mitochondrial respiration, mitochondrial function, immunoblotting, and immunofluorescence analysis of synaptic and mitophagy proteins and the colocalization of Rlip and mTau proteins. We found Rlip protein levels were reduced in mTau-HT22 cells, Rlip silenced HT22 cells, and mTau + Rlip RNA silenced HT22 cells; on the other hand, increased Rlip levels were observed in Rlip cDNA transfected HT22 cells. We found cell survival was decreased in mTau-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mTau-HT22 cells. A significantly reduced oxygen consumption rate (OCR) was found in mTau-HT22 cells and in RNA-silenced Rlip-HT22 cells, with an even greater reduction in mTau-HT22 + Rlip RNA-silenced HT22 cells. A significantly increased OCR was found in Rlip-overexpressed HT22 cells and in all groups of cells that overexpress Rlip cDNA. Mitochondrial function was defective in mTau-HT22 cells, RNA silenced Rlip in HT22 cells, and was further defective in mTau-HT22 + Rlip RNA-silenced HT22 cells; however, it was rescued in Rlip overexpressed in all groups of HT22 cells. Synaptic and mitophagy proteins were decreased in mTau-HT22 cells, and further reductions were found in RNA-silenced mTau-HT22 cells. However, these were increased in mTau + Rlip-overexpressed HT22 cells. An increased number of mitochondria and decreased mitochondrial length were found in mTau-HT22 cells. These were rescued in Rlip-overexpressed mTau-HT22 cells. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reverses these defects. Overall, our findings revealed that Rlip is a promising new target for aging, AD, and other tauopathies/neurological diseases.

Keywords:  Rlip deficiency; mitochondrial function; mitophagy; mutant Tau; oxygen consumption rate; phosphorylated tau

DOI:  https://doi.org/10.3390/cells12121646
Antioxidants (Basel). 2023 May 27. pii: 1163. [Epub ahead of print]12(6):

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies.

Tianzheng Yu, Li Wang, Lei Zhang, Patricia A Deuster.

  Mitochondrial fission is a crucial process in maintaining metabolic homeostasis in normal physiology and under conditions of stress. Its dysregulation has been associated with several metabolic diseases, including, but not limited to, obesity, type 2 diabetes (T2DM), and cardiovascular diseases. Reactive oxygen species (ROS) serve a vital role in the genesis of these conditions, and mitochondria are both the main sites of ROS production and the primary targets of ROS. In this review, we explore the physiological and pathological roles of mitochondrial fission, its regulation by dynamin-related protein 1 (Drp1), and the interplay between ROS and mitochondria in health and metabolic diseases. We also discuss the potential therapeutic strategies of targeting mitochondrial fission through antioxidant treatments for ROS-induced conditions, including the effects of lifestyle interventions, dietary supplements, and chemicals, such as mitochondrial division inhibitor-1 (Mdivi-1) and other mitochondrial fission inhibitors, as well as certain commonly used drugs for metabolic diseases. This review highlights the importance of understanding the role of mitochondrial fission in health and metabolic diseases, and the potential of targeting mitochondrial fission as a therapeutic approach to protecting against these conditions.

Keywords:  Coenzyme Q10; Drp1; L-citrulline; astaxanthin; curcumin; exercise; lifestyle interventions; mitochondrial integrity; pharmacological management; reactive oxygen species; resveratrol

DOI:  https://doi.org/10.3390/antiox12061163
J Cell Physiol. 2023 Jun 25.

Epigenetic regulation of mitochondrial-endoplasmic reticulum dynamics in kidney diseases.

Vishwadeep Shelke, Vinayak Yelgonde, Ajinath Kale, Maciej Lech, Anil Bhanudas Gaikwad.

  Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney dysfunction demand an intensified effort toward more effective prevention and treatment. The pathophysiology of kidney diseases is complex and comprises diverse organelle dysfunctions including mitochondria and endoplasmic reticulum (ER). The recent findings prove interactions between the ER membrane and nearly all cell compartments and give new insights into molecular events involved in cellular mechanisms in health and disease. Interactions between the ER and mitochondrial membranes, known as the mitochondria-ER contacts regulate kidney physiology by interacting with each other via membrane contact sites (MCS). ER controls mitochondrial dynamics through ER stress sensor proteins or by direct communication via mitochondria-associated ER membrane to activate signaling pathways such as apoptosis, calcium transport, and autophagy. More importantly, these organelle dynamics are found to be regulated by several epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs and can be a potential therapeutic target against kidney diseases. However, a thorough understanding of the role of epigenetic regulation of organelle dynamics and their functions is not well understood. Therefore, this review will unveil the role of epigenetic mechanisms in regulating organelle dynamics during various types of kidney diseases. Moreover, we will also shed light on different stress origins in organelles leading to kidney disease. Henceforth, by understanding this we can target epigenetic mechanisms to maintain/control organelle dynamics and serve them as a novel therapeutic approach against kidney diseases.

Keywords:  endoplasmic reticulum; epigenetics; kidney diseases; mitochondria; organelle dynamics

DOI:  https://doi.org/10.1002/jcp.31058
Antioxidants (Basel). 2023 Jun 06. pii: 1225. [Epub ahead of print]12(6):

Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress.

Winston J T Tan, Joseph Santos-Sacchi, Jane Tonello, Anil Shanker, Alla V Ivanova.

  Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, and altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether the pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1/Tusc2-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed the dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and the cochlear hypothalamic-pituitary-adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins and calcium-linked transporters and voltage-gated channels. These findings suggest that the pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss.

Keywords:  2-DG; 2-deoxy-D-glucose; Fus1/Tusc2; Seahorse analysis; age-related hearing loss; cochlea; mitochondria; mitochondrial dysfunction; oxidative stress; rapamycin

DOI:  https://doi.org/10.3390/antiox12061225