bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–08–14
25 papers selected by
Catalina Vasilescu, University of Helsinki
  1. Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
  2. Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function.
  3. Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes.
  4. Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.
  5. Lipid droplets promote efficient mitophagy.
  6. Mitofusin 2 Integrates Mitochondrial Network Remodelling, Mitophagy and Renewal of Respiratory Chain Proteins in Neurons after Oxygen and Glucose Deprivation.
  7. High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells.
  8. Targeting Mitochondria as a Therapeutic Approach for Parkinson's Disease.
  9. High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.
  10. The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.
  11. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion.
  12. OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.
  13. Cooperative assembly of the mitochondrial respiratory chain.
  14. Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle.
  15. The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS.
  16. mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases.
  17. The 5'-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance nuclease 1 (MGME1).
  18. The Mitochondrial NAD Kinase Functions as a Major Metabolic Regulator Upon Increased Energy Demand.
  19. Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study.
  20. The multi-faced role of FUNDC1 in mitochondrial events and human diseases.
  21. NAD+ to assess health in aging humans.
  22. Enhanced rare disease mapping for phenome-wide genetic association in the UK Biobank.
  23. IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter.
  24. Macrophages induce cardiomyocyte ferroptosis via mitochondrial transfer.
  25. Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells.
  1. Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00129-6. [Epub ahead of print] 101560
    Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
    Patrick M Schaefer, Jessica Huang, Arrienne Butic, Caroline Perry, Tal Yardeni, Wendy Tan, Ryan Morrow, Joseph A Baur, Douglas C Wallace.
       OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.
    METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
    RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
    CONCLUSION: Increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.
    Keywords:  Exercise; Mitochondrial disorder; NAD(+)/NADH; Nicotinamide riboside
    DOI:  https://doi.org/10.1016/j.molmet.2022.101560
  2. FEBS J. 2022 Aug 13.
    Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function.
    Harrison Burgin, Alice J Sharpe, Shuai Nie, Mark Ziemann, Jordan J Crameri, Diana Stojanovski, James Pitt, Akira Ohtake, Kei Murayama, Matthew McKenzie.
      Short chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short chain enoyl-CoA esters to short chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell 'knockout' model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 'knockout' cells showed reductions in key mitochondrial pathways, including the TCA cycle, receptor mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid β-oxidation. Functional analysis of ECHS1 'knockout' cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 'knockout' cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2 , complex IV, complex V and supercomplexes CIII2 /CIV and CI/CIII2 /CIV), which were associated with a defect in complex I assembly. Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2 , CIV, CV and the CI/CIII2 /CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D.
    Keywords:  ECHS1 deficiency; OXPHOS; fatty acid oxidation; mitochondria; mitochondrial disease; short chain enoyl-CoA hydratase
    DOI:  https://doi.org/10.1111/febs.16595
  3. Genome Biol. 2022 Aug 09. 23(1): 170
    Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes.
    Iliana Soto, Mary Couvillion, Katja G Hansen, Erik McShane, J Conor Moran, Antoni Barrientos, L Stirling Churchman.
       BACKGROUND: Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome.
    RESULTS: We resolve features of mitochondrial translation initiation and identify a small ORF in the 3' UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways.
    CONCLUSIONS: Based on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability.
    DOI:  https://doi.org/10.1186/s13059-022-02732-9
  4. Hum Mol Genet. 2022 Aug 10. pii: ddac190. [Epub ahead of print]
    Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.
    Zhipeng Nie, Chenhui Wang, Jiarong Chen, Yanchun Ji, Hongxing Zhang, Fuxin Zhao, Xiangtian Zhou, Min-Xin Guan.
      Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that results from degeneration of retinal ganglion cells (RGC). Mitochondrial ND4 11778G > A mutation, which affects structural components of complex I, is the most prevalent LHON-associated mitochondrial DNA (mtDNA) mutation worldwide. The m.11778G > A mutation is the primary contributor underlying the development of LHON and X-linked PRICKLE3 allele (c.157C > T, p.Arg53Trp) linked to biogenesis of ATPase interacts with m.11778G > A mutation to cause LHON. However, the lack of appropriate cell and animal models of LHON has been significant obstacles for deep elucidation of disease pathophysiology, specifically the tissue specific effects. Using RGC-like cells differentiated from induced pluripotent stem cells (iPSCs) from members of one Chinese family (asymptomatic subjects carrying only m.11778G > A mutation or PRICKLE3 p.Arg53Trp mutation, symptomatic individuals bearing both m.11778G > A and PRICKLE3 p.Arg53Trp mutations and control lacking these mutations), we demonstrated the deleterious effects of mitochondrial dysfunctions on the morphology and functions of RGCs. Notably, iPSCs bearing only m.11778G > A or p.Arg53Trp mutation exhibited mild defects in differentiation to RGC-like cells. The RGC-like cells carrying only m.11778G > A or p.Arg53Trp mutation displayed mild defects in RGC morphology, including the area of soma and numbers of neurites, electrophysiological properties, ATP production and apoptosis. Strikingly, those RGC-like cells derived from symptomatic individuals harboring both m.11778G > A and p.Arg53Trp mutations displayed greater defects in the development, morphology and functions than those in cells bearing single mutation. These findings provide new insights into pathophysiology of LHON arising from RGC deficiencies caused by synergy between m.11778G > A and PRICKLE3 p.Arg53Trp mutation.
    DOI:  https://doi.org/10.1093/hmg/ddac190
  5. Autophagy. 2022 Aug 08. 1-2
    Lipid droplets promote efficient mitophagy.
    Maeve Long, Thomas G McWilliams.
      Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.
    Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2089956
  6. Mol Neurobiol. 2022 Aug 13.
    Mitofusin 2 Integrates Mitochondrial Network Remodelling, Mitophagy and Renewal of Respiratory Chain Proteins in Neurons after Oxygen and Glucose Deprivation.
    Piotr Wojtyniak, Anna Boratynska-Jasinska, Karolina Serwach, Joanna Gruszczynska-Biegala, Barbara Zablocka, Jacek Jaworski, Maria Kawalec.
      In attempts to develop effective therapeutic strategies to limit post-ischemic injury, mitochondria emerge as a key element determining neuronal fate. Mitochondrial damage can be alleviated by various mechanisms including mitochondrial network remodelling, mitochondrial elimination and mitochondrial protein biogenesis. However, the mechanisms regulating relationships between these phenomena are poorly understood. We hypothesized that mitofusin 2 (Mfn2), a mitochondrial GTPase involved in mitochondrial fusion, mitochondria trafficking and mitochondria and endoplasmic reticulum (ER) tethering, may act as one of linking and regulatory factors in neurons following ischemic insult. To verify this assumption, we performed temporal oxygen and glucose deprivation (OGD/R) on rat cortical primary culture to determine whether Mfn2 protein reduction affected the onset of mitophagy, subsequent mitochondrial biogenesis and thus neuronal survival. We found that Mfn2 knockdown increased neuronal susceptibility to OGD/R, prevented mitochondrial network remodelling and resulted in prolonged mitophagosomes formation in response to the insult. Next, Mfn2 knockdown was observed to be accompanied by reduced Parkin protein levels and increased Parkin accumulation on mitochondria. As for wild-type neurons, OGD/R insult was followed by an elevated mtDNA content and an increase in respiratory chain proteins. Neither of these phenomena were observed for Mfn2 knockdown neurons. Collectively, our findings showed that Mfn2 in neurons affected their response to mild and transient OGD stress, balancing the extent of defective mitochondria elimination and positively influencing mitochondrial respiratory protein levels. Our study suggests that Mfn2 is one of essential elements for neuronal response to ischemic insult, necessary for neuronal survival.
    Keywords:  Brain ischemia; Mitochondria; Mitochondrial DNA; Mitochondrial biogenesis; Mitofusin 2; Mitophagy; Primary neurons
    DOI:  https://doi.org/10.1007/s12035-022-02981-6
  7. STAR Protoc. 2022 Sep 16. 3(3): 101602
    High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells.
    Annika Zink, Undine Haferkamp, Annika Wittich, Mathias Beller, Ole Pless, Alessandro Prigione.
      We present a high-content screening (HCS) protocol for quantifying mitochondrial activity in live neural cells from human induced pluripotent stem cells (iPSCs). The assessment is based on mitochondrial membrane potential, which is influenced by the efficiency of mitochondrial bioenergetics. We describe how to perform the analysis using both an HCS platform and the open-source software CellProfiler. The protocol can identify the mitochondrial fitness of human neurons and may be used to carry out high-throughput compound screenings in patient-derived neural cells. For complete details on the use and execution of this protocol, please refer to Lorenz et al. (2017) and Zink et al. (2020).
    Keywords:  Cell Biology; Cell-based Assays; Metabolism; Microscopy; Neuroscience; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101602
  8. Cell Mol Neurobiol. 2022 Aug 11.
    Targeting Mitochondria as a Therapeutic Approach for Parkinson's Disease.
    Maryam Abrishamdar, Maryam Sadat Jalali, Yaghoob Farbood.
      Neurodegeneration is among the most critical challenges that involve modern societies and annually influences millions of patients worldwide. While the pathophysiology of Parkinson's disease (PD) is complicated, the role of mitochondrial is demonstrated. The in vitro and in vivo models and genome-wide association studies in human cases proved that specific genes, including PINK1, Parkin, DJ-1, SNCA, and LRRK2, linked mitochondrial dysfunction with PD. Also, mitochondrial DNA (mtDNA) plays an essential role in the pathophysiology of PD. Targeting mitochondria as a therapeutic approach to inhibit or slow down PD formation and progression seems to be an exciting issue. The current review summarized known mutations associated with both mitochondrial dysfunction and PD. The significance of mtDNA in Parkinson's disease pathogenesis and potential PD therapeutic approaches targeting mitochondrial dysfunction was then discussed.
    Keywords:  Mitochondrial dysfunction; Neurodegeneration; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s10571-022-01265-w
  9. Geroscience. 2022 Aug 10.
    High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.
    Brenda Gonzalez, Archana Tare, Seungjin Ryu, Simon C Johnson, Gil Atzmon, Nir Barzilai, Matt Kaeberlein, Yousin Suh.
      Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.
    Keywords:  Aging; Centenarian; Genetic variant; Longevity; Mitochondria
    DOI:  https://doi.org/10.1007/s11357-022-00634-z
  10. Metabolism. 2022 Aug 04. pii: S0026-0495(22)00153-6. [Epub ahead of print]135 155275
    The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.
    Zhiyao Fu, Hyunbae Kim, Paul T Morse, Mu-Jie Lu, Maik Hüttemann, Xiaolu A Cambronne, Kezhong Zhang, Ren Zhang.
       INTRODUCTION: Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism and energy production. NAD+-dependent deacetylase sirtuin 3 (SIRT3) regulates the acetylation levels of mitochondrial proteins that are involved in mitochondrial homeostasis. Fasting up-regulates hepatic SIRT3 activity, which requires mitochondrial NAD+. What is the mechanism, then, to transport more NAD+ into mitochondria to sustain enhanced SIRT3 activity during fasting?
    OBJECTIVE: SLC25A51 is a recently discovered mitochondrial NAD+ transporter. We tested the hypothesis that, during fasting, increased expression of SLC25A51 is needed for enhanced mitochondrial NAD+ uptake to sustain SIRT3 activity. Because the fasting-fed cycle and circadian rhythm are closely linked, we further tested the hypothesis that SLC25A51 is a circadian regulated gene.
    METHODS: We examined Slc25a51 expression in the liver of fasted mice, and examined its circadian rhythm in wild-type mice and those with liver-specific deletion of the clock gene BMAL1 (LKO). We suppressed Slc25a51 expression in hepatocytes and the mouse liver using shRNA-mediated knockdown, and then examined mitochondrial NAD+ levels, SIRT3 activities, and acetylation levels of SIRT3 target proteins (IDH2 and ACADL). We measured mitochondrial oxygen consumption rate using Seahorse analysis in hepatocytes with reduced Slc25a51 expression.
    RESULTS: We found that fasting induced the hepatic expression of Slc25a51, and its expression showed a circadian rhythm-like pattern that was disrupted in LKO mice. Reduced expression of Slc25a51 in hepatocytes decreased mitochondrial NAD+ levels and SIRT3 activity, reflected by increased acetylation of SIRT3 targets. Slc25a51 knockdown reduced the oxygen consumption rate in intact hepatocytes. Mice with reduced Slc25a51 expression in the liver manifested reduced hepatic mitochondrial NAD+ levels, hepatic steatosis and hypertriglyceridemia.
    CONCLUSIONS: Slc25a51 is a fasting-induced gene that is needed for hepatic SIRT3 functions.
    Keywords:  Mitochondria; NAD; SIRT3; SLC25A51
    DOI:  https://doi.org/10.1016/j.metabol.2022.155275
  11. Nucleic Acids Res. 2022 Aug 10. pii: gkac661. [Epub ahead of print]
    Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion.
    Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J Siira, Louise Jenninger, Aleksandra Filipovska, Anders R Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson.
      The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.
    DOI:  https://doi.org/10.1093/nar/gkac661
  12. Trends Endocrinol Metab. 2022 Aug 06. pii: S1043-2760(22)00134-5. [Epub ahead of print]
    OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.
    John Noone, Donal J O'Gorman, Helena C Kenny.
      The mitochondria are double-membrane organelles integral for energy metabolism. Mitochondrial dynamics is regulated by inner and outer mitochondrial membrane (IMM and OMM) proteins, which promote fission and fusion. Optic atrophy 1 (OPA1) regulates IMM fusion, prevents apoptosis, and is a key regulator of morphological change in skeletal and cardiac muscle physiology and pathophysiology. OPA1 fuses the inner membranes of adjacent mitochondria, allowing for an increase in oxidative phosphorylation (OXPHOS). Considering the importance of energy metabolism in whole-body physiology, OPA1 and its regulators have been proposed as novel targets for the treatment of skeletal muscle atrophy and heart failure. Here, we review the role and regulation of OPA1 in skeletal muscle and cardiac pathophysiology, epitomizing its critical role in the cell.
    Keywords:  exercise; heart; metabolism; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1016/j.tem.2022.07.003
  13. Trends Biochem Sci. 2022 Aug 09. pii: S0968-0004(22)00187-6. [Epub ahead of print]
    Cooperative assembly of the mitochondrial respiratory chain.
    Erika Fernández-Vizarra, Cristina Ugalde.
      Deep understanding of the pathophysiological role of the mitochondrial respiratory chain (MRC) relies on a well-grounded model explaining how its biogenesis is regulated. The lack of a consistent framework to clarify the modes and mechanisms governing the assembly of the MRC complexes and supercomplexes (SCs) works against progress in the field. The plasticity model was postulated as an attempt to explain the coexistence of mammalian MRC complexes as individual entities and associated in SC species. However, mounting data accumulated throughout the years question the universal validity of the plasticity model as originally proposed. Instead, as we argue here, a cooperative assembly model provides a much better explanation to the phenomena observed when studying MRC biogenesis in physiological and pathological settings.
    Keywords:  assembly factors; cooperative assembly model; mitochondria; plasticity model; respiratory chain organization; supercomplexes
    DOI:  https://doi.org/10.1016/j.tibs.2022.07.005
  14. Front Physiol. 2022 ;13 898792
    Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle.
    Juan Diego Hernández-Camacho, Daniel J M Fernández-Ayala, Cristina Vicente-García, Ignacio Navas-Enamorado, Guillermo López-Lluch, Clara Oliva, Rafael Artuch, Judith Garcia-Villoria, Antonia Ribes, Rafael de Cabo, Jaime J Carvajal, Plácido Navas.
      ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.
    Keywords:  coenzyme Q; fatty acids; food deprivation; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fphys.2022.898792
  15. Int J Mol Sci. 2022 Aug 03. pii: 8634. [Epub ahead of print]23(15):
    The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS.
    Yujie Zou, Jingwen Pei, Yushu Wang, Qin Chen, Minli Sun, Lulu Kang, Xuyuan Zhang, Liguo Zhang, Xiang Gao, Zhaoyu Lin.
      Deficiency in scavenger receptor class B, member 2 (SCARB2) is related to both Gaucher disease (GD) and Parkinson's disease (PD), which are both neurodegenerative-related diseases without cure. Although both diseases lead to weight loss, which affects the quality of life and the progress of diseases, the underlying molecular mechanism is still unclear. In this study, we found that Scarb2-/- mice showed significantly reduced lipid storage in white fat tissues (WAT) compared to WT mice on a regular chow diet. However, the phenotype is independent of heat production, activity, food intake or energy absorption. Furthermore, adipocyte differentiation and cholesterol homeostasis were unaffected. We found that the impaired lipid accumulation of Adiponectin-cre; Scarb2fl/fl mice was due to the imbalance between glycolysis and oxidative phosphorylation (OXPHOS). Mechanistically, the mechanistic target of rapamycin complex 1 (mTORC1)/ eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) pathway was down-regulated in Scarb2 deficient adipocytes, leading to impaired mitochondrial respiration and enhanced glycolysis. Altogether, we reveal the role of SCARB2 in metabolism regulation besides the nervous system, which provides a theoretical basis for weight loss treatment of patients with neurodegenerative diseases.
    Keywords:  LIMP-2 (SCARB2); OXPHOS; glycolysis; lysosomes; mTORC1/4E-BP1; mitochondria
    DOI:  https://doi.org/10.3390/ijms23158634
  16. Curr Neuropharmacol. 2022 Aug 10.
    mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases.
    Dehao Shang, Minghao Huang, Biyao Wang, Xu Yan, Zhou Wu, Xinwen Zhang.
      Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Mitochondrial DNA (mtDNA); Mitophagy; Parkinson’s disease; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.2174/1570159X20666220810114644
  17. J Biol Chem. 2022 Aug 04. pii: S0021-9258(22)00748-7. [Epub ahead of print] 102306
    The 5'-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance nuclease 1 (MGME1).
    Kathleen M Urrutia, Wenyan Xu, Linlin Zhao.
      In higher eukaryotes, mitochondria play multiple roles in energy production, signaling, and biosynthesis. Mitochondria possess multiple copies of mitochondrial DNA (mtDNA), which encodes 37 genes that are essential for mitochondrial and cellular function. When mtDNA is challenged by endogenous and exogenous factors, mtDNA undergoes repair, degradation, and compensatory synthesis. mtDNA degradation is an emerging pathway in mtDNA damage response and maintenance. A key factor involved is the human mitochondrial genome maintenance nuclease 1 (MGME1). Despite previous biochemical and functional studies, controversies exist regarding the polarity of MGME1-mediated DNA cleavage. Also, how DNA sequence may affect the activities of MGME1 remains elusive. Such information is not only fundamental to the understanding of MGME1 but also critical for deciphering the mechanism of mtDNA degradation. Herein, we use quantitative assays to examine the effects of substrate structure and sequence on the DNA-binding and enzymatic activities of MGME1. We demonstrate that MGME1 binds to and cleaves from the 5'-end of single-stranded DNA substrates, especially in the presence of 5'-phosphate, which plays an important role in DNA-binding and optimal cleavage by MGME1. Additionally, MGME1 can tolerate certain modifications at the terminal end, such as a 5'-deoxyribosephosphate (5'dRp) intermediate formed in base excision repair (BER). We show MGME1 processes different sequences with varying efficiencies, with dT- and dC-sequences being the most and least efficiently digested, respectively. Our results provide insights into the enzymatic properties of MGME1 and a rationale for the coordination of MGME1 with the 3'-5' exonuclease activity of DNA polymerase γ in mtDNA degradation.
    Keywords:  DNA damage; DNA enzyme; DNA repair; DNA turnover; mitochondrial DNA (mtDNA)
    DOI:  https://doi.org/10.1016/j.jbc.2022.102306
  18. Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00131-4. [Epub ahead of print] 101562
    The Mitochondrial NAD Kinase Functions as a Major Metabolic Regulator Upon Increased Energy Demand.
    Hyunbae Kim, Zhiyao Fu, Zhao Yang, Zhenfeng Song, El Hussain Shamsa, Thangal Yumnamcha, Shengyi Sun, Wanqing Liu, Ahmed S Ibrahim, Nathan R Qi, Ren Zhang, Kezhong Zhang.
      The mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (MNADK) mediates de novo mitochondrial NADP biosynthesis by catalyzing the phosphorylation of NAD to yield NADP. In this study, we investigated the function and mechanistic basis by which MNADK regulates metabolic homeostasis. Generalized gene-set analysis by aggregating human patient genomic databases indicated that human MNADK common gene variants or decreased expression of the gene are significantly associated with the occurrence of type-2 diabetes, non-alcoholic fatty liver disease (NAFLD), or hepatocellular carcinoma (HCC). Ablation of the MNADK gene in mice led to decreased fat oxidation, coincident with increased respiratory exchange ratio (RER) and decreased energy expenditure upon energy demand triggered by endurance exercise or fasting. On an atherogenic high-fat diet (HFD), MNADK-null mice exhibited hepatic insulin resistance and glucose intolerance, indicating a type-2 diabetes-like phenotype in the absence of MNADK. Further investigation revealed that MNADK deficiency led to a decrease in mitochondrial NADP(H) but an increase in cellular reactive oxygen species (ROS) in mouse livers. Consistently, protein levels of the major metabolic regulators or enzymes were decreased, while their acetylation modifications were increased in the livers of MNADK-null mice. Further, feeding mice with a HFD caused S-nitrosylation (SNO) modification, a posttranslational modification that represses protein activities, on MNADK protein in the liver. Reconstitution of an SNO-resistant MNADK variant, MNADK-S193, into MNADK-null mice mitigated hepatic steatosis induced by HFD. In summary, our studies define that MNADK, the only known mammalian mitochondrial NAD kinase, plays important roles in preserving energy homeostasis to mitigate the risk of metabolic disorders.
    DOI:  https://doi.org/10.1016/j.molmet.2022.101562
  19. Orphanet J Rare Dis. 2022 Aug 09. 17(1): 310
    Vitamin B12 in Leber hereditary optic neuropathy mutation carriers: a prospective cohort study.
    Julia Zibold, Bettina von Livonius, Hana Kolarova, Günter Rudolph, Claudia S Priglinger, Thomas Klopstock, Claudia B Catarino.
       BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center.
    METHODS: From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201-339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine.
    RESULTS: We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5-82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5-7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05).
    CONCLUSIONS: The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.
    Keywords:  Cobalamin; Hereditary optic atrophy; LHON; Leber optic atrophy; Mitochondrial disease; Vitamin B12
    DOI:  https://doi.org/10.1186/s13023-022-02453-z
  20. Front Cell Dev Biol. 2022 ;10 918943
    The multi-faced role of FUNDC1 in mitochondrial events and human diseases.
    Nannan Tan, Tianhua Liu, Xiaoping Wang, Mingyan Shao, Miao Zhang, Weili Li, Guanjing Ling, Jinchi Jiang, Qiyan Wang, Jing Li, Chun Li, Wei Wang, Yong Wang.
      Mitophagy plays a vital role in the selective elimination of dysfunctional and unwanted mitochondria. As a receptor of mitophagy, FUN14 domain containing 1 (FUNDC1) is attracting considerably critical attention. FUNDC1 is involved in the mitochondria fission, the clearance of unfolded protein, iron metabolism in mitochondria, and the crosstalk between mitochondria and endoplasmic reticulum besides mitophagy. Studies have demonstrated that FUNDC1 is associated with the progression of ischemic disease, cancer, and metabolic disease. In this review, we systematically examine the recent advancements in FUNDC1 and the implications of this protein in health and disease.
    Keywords:  FUNDC1; I/R injury; endoplasmic reticulum; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2022.918943
  21. Aging (Albany NY). 2022 Aug 06. undefined(undefined):
    NAD+ to assess health in aging humans.
    Georges E Janssens, Riekelt H Houtkooper, Joris Hoeks.
      
    Keywords:  NAD +; aging; exercise; frailty; healthspan
    DOI:  https://doi.org/10.18632/aging.204220
  22. Genome Med. 2022 Aug 09. 14(1): 85
    Enhanced rare disease mapping for phenome-wide genetic association in the UK Biobank.
    Matthew T Patrick, Redina Bardhi, Wei Zhou, James T Elder, Johann E Gudjonsson, Lam C Tsoi.
       BACKGROUND: Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population.
    METHODS: We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease.
    RESULTS: Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10-13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10-13). We constructed an interactive resource highlighting demographic information ( http://www-personal.umich.edu/~mattpat/rareDiseases.html ) and demonstrate transferability by applying our mapping to a medical claims database.
    CONCLUSIONS: Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases.
    Keywords:  Demographics; Genetic associations; Phenotyping; Rare disease; UK Biobank
    DOI:  https://doi.org/10.1186/s13073-022-01094-y
  23. Proc Natl Acad Sci U S A. 2022 Aug 16. 119(33): e2121040119
    IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter.
    Maxim Katsenelson, Ilana Shapira, Eman Abbas, Kristina Jevdokimenko, Boaz Styr, Antonella Ruggiero, Saba Aïd, Eugenio F Fornasiero, Martin Holzenberger, Silvio O Rizzoli, Inna Slutsky.
      Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling a network-wide homeostatic response remains largely unknown. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response to inactivity, without altering the distribution of baseline firing rates. The deficient firing rate homeostatic response was due to disruption of both postsynaptic and intrinsic plasticity. At the cellular level, we detected a fraction of IGF-1Rs in mitochondria, colocalized with the mitochondrial calcium uniporter complex (MCUc). IGF-1R deletion suppressed transcription of the MCUc members and burst-evoked mitochondrial Ca2+ (mitoCa2+) by weakening mitochondria-to-cytosol Ca2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R-deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa2+ coupling and firing rate homeostasis. Our findings indicate that mitochondrial IGF-1R is a key regulator of the integrated homeostatic response by tuning the reliability of burst transfer by MCUc. Based on these results, we propose that MCUc acts as a homeostatic Ca2+ sensor. Faulty activation of MCUc may drive dysregulation of firing rate homeostasis in aging and in brain disorders associated with aberrant IGF-1R/MCUc signaling.
    Keywords:  IGF-1 receptor; MCU; firing rate homeostasis; homeostatic plasticity; mitochonria
    DOI:  https://doi.org/10.1073/pnas.2121040119
  24. Free Radic Biol Med. 2022 Aug 03. pii: S0891-5849(22)00498-1. [Epub ahead of print]190 1-14
    Macrophages induce cardiomyocyte ferroptosis via mitochondrial transfer.
    Jun Chen, Chun-Yan Fu, Gerong Shen, Jingyu Wang, Lintao Xu, Heyangzi Li, Xi Cao, Ming-Zhi Zheng, Yue-Liang Shen, Jinjie Zhong, Ying-Ying Chen, Lin-Lin Wang.
       INTRODUCTION: Mitochondrial transfer is a new cell-to-cell communication manner. Whether the mitochondrial transfer is also involved in the macrophage infiltration-induced cardiac injury is unclear.
    OBJECTIVES: This study aimed to determine whether macrophage mitochondria can be transferred to cardiomyocytes, and to investigate its possible role and mechanism.
    METHODS: Mitochondrial transfer between macrophages and cardiomyocytes was detected using immunofluorescence staining and flow cytometry. Cellular metabolites were analyzed using LC-MS technique. Differentially expressed mRNAs were identified using RNA-seq technique.
    RESULTS: (1) After cardiomyocytes were cultured with macrophage-conditioned medium (COND + group), macrophage-derived mitochondria have been found in cardiomyocytes, which could be blocked by dynasore (an inhibitor of clathrin-mediated endocytosis). (2) Compared with control (CM) group, there were 545 altered metabolites found in COND + group, most of which were lipids and lipid-like molecules. The altered metabolites were mainly enriched in the β-oxidation of fatty acids and glutathione metabolism. And there were 4824 differentially expressed mRNAs, which were highly enriched in processes like lipid metabolism-associated pathway. (3) Both RNA-seq and qRT-PCR results found that ferroptosis-related mRNAs such as Ptgs2 and Acsl4 increased, and Gpx4 mRNA decreased in COND + group (P < 0.05 vs CM group). (4) The levels of cellular free Fe2+ and mitochondrial lipid peroxidation were increased; while GSH/GSSG ratio, mitochondrial aspect ratio, mitochondrial membrane potential, and ATP production were decreased in cardiomyocytes of COND + group (P < 0.05 vs CM group). All the above phenomena could be blocked by a ferroptosis inhibitor ferrostatin-1 (P < 0.05).
    CONCLUSION: Macrophages could transfer mitochondria to cardiomyocytes. Macrophage-derived mitochondria were internalized into cardiomyocytes through clathrin- and/or lipid raft-mediated endocytosis. Uptake of exogenous macrophage mitochondria induced cardiomyocyte injury via triggering ferroptosis.
    Keywords:  Cardiomyocytes; Ferroptosis; Macrophages; Mitochondrial transfer
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.07.015
  25. Nat Genet. 2022 Aug 11.
    Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells.
    Foad J Rouhani, Xueqing Zou, Petr Danecek, Cherif Badja, Tauanne Dias Amarante, Gene Koh, Qianxin Wu, Yasin Memari, Richard Durbin, Inigo Martincorena, Andrew R Bassett, Daniel Gaffney, Serena Nik-Zainal.
      We explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs.
    DOI:  https://doi.org/10.1038/s41588-022-01147-3
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