bims-mitmed 2021-10-31 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2021‒10‒31
27 papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico

Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain.
The Natural History of Leigh Syndrome: A Study of Disease Burden and Progression.
Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome.
Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers' Syndrome Genotypes.
Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.
The function of Scox in glial cells is essential for locomotive ability in Drosophila.
Adult-onset, isolated respiratory chain complex-IV deficiency with mild manifestations.
Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and subsequent mitochondrial accumulation in human fibroblasts.
It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.
Migratory Rolandic Encephalopathy Caused by the Mitochondrial ND3 Mutation.
Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations.
Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3.
The HO-1/CO System and Mitochondrial Quality Control in Skeletal Muscle.
Determining Mitochondrial 3243A>G Heteroplasmy Using an ARMS-ddPCR Strategy.
Players in Mitochondrial Dynamics and Female Reproduction.
Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2.
Current and Future Treatment Approaches for Barth Syndrome.
The many roles mitochondria play in mammalian aging.
MuSK not MNGIE: Atypical MuSK-antibody myasthenia presenting as a genetic disorder.
Charcot-Marie-Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy.
Quantitative Craniofacial Analysis and Generation of Human Induced Pluripotent Stem Cells for Muenke Syndrome: A Case Report.
Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies.
Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice.
A subpopulation of arenavirus nucleoprotein localizes to mitochondria.
The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis.
Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy.
Mitochondrial calcium exchange in physiology and disease.

Dev Cell. 2021 Oct 22. pii: S1534-5807(21)00809-1. [Epub ahead of print]

Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain.

Shefali Krishna, Rafael Arrojo E Drigo, Juliana S Capitanio, Ranjan Ramachandra, Mark Ellisman, Martin W Hetzer.

  In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.

Keywords:  age mosaicism; aging; electron transport chain; heterogeneity; long-lived proteins; mitochondria; muscle; neurons; protein homeostasis; supercomplexes

DOI:  https://doi.org/10.1016/j.devcel.2021.10.008
Ann Neurol. 2021 Oct 30.

The Natural History of Leigh Syndrome: A Study of Disease Burden and Progression.

Albert Z Lim, Yi Shiau Ng, Alasdair Blain, Cecilia Jiminez-Moreno, Charlotte L Alston, Victoria Nesbitt, Louise Simmons, Saikat Santra, Evangeline Wassmer, Emma L Blakely, Doug M Turnbull, Robert W Taylor, Gráinne S Gorman, Robert McFarland.

OBJECTIVE: This observational cohort study aims to quantify disease burden over time, establish disease progression rates and identify factors that may determine the disease course of Leigh syndrome.METHODS: Seventy-two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scales (NPMDS) at baseline 3.7 years (IQR 2.0-7.6) and follow-up assessments 7.5 years (IQR 3.7-11.0) in clinics were enrolled. 82% of this cohort had a confirmed genetic diagnosis with pathogenic variants in the MT-ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0-14), moderate (15-25) and severe (>25) disease burden. Detailed clinical, neuroradiological and molecular genetic findings were also analysed.
RESULTS: The median total NPMDS scores rose significantly (Z=-6.9, p<0.001) and the percentage of children with severe disease burden doubled (22%→42%) over 2.6 years of follow-up. Poor function (especially mobility, self-care, communication, feeding and education) and extrapyramidal features contributed significantly to the disease burden (τb ≈0.45-0.68, p<0.001). These children also deteriorated to wheelchair dependence (31%→57%), exclusive enteral feeding (22%→46%) and one-to-one assistance for self-care (25%→43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow-up NPMDS scores (disease burden) (p<0.001) and steeper increase in NPMDS score per annum (disease progression) (p<0.001). Other predictors of poor outcomes include SURF1 gene variants (p<0.001) and bilateral caudate changes on neuroimaging (p<0.01).
INTERPRETATION: This study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26260
Mol Ther Methods Clin Dev. 2021 Dec 10. 23 158-168

Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome.

Qinglan Ling, Matthew Rioux, Yuhui Hu, MinJae Lee, Steven J Gray.

  SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.

Keywords:  AAV; Leigh syndrome; SURF1; adeno-associated virus; gene therapy

DOI:  https://doi.org/10.1016/j.omtm.2021.09.001
Front Pharmacol. 2021 ;12 669516

Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers' Syndrome Genotypes.

Hua Li, Wei Wang, Xiaodi Han, Yujia Zhang, Lifang Dai, Manting Xu, Jie Deng, Changhong Ding, Xiaohui Wang, Chunhong Chen, Xiaofeng Yang, Fang Fang.

  Alpers' syndrome is an early inceptive neurodegenerative disorder with a poor prognosis, characterized by developmental regression, intractable epilepsy, and hepatic dysfunction. Candidate genes, such as POLG, PARS2, CARS2, FARS2, NARS2, and GABRB2 are distinguished and registered following research on large cohorts that portray the clinical phenotype in such patients using expanded access to whole-exome sequencing (WES). In this study, we aimed to better understand the electroencephalogram (EEG) characteristics and clinical phenotype of different genotypes of the Alpers' syndrome, which are currently insufficiently studied. We conducted a study on seven patients with Alpers' syndrome who received treatment in Beijing Children's Hospital and had a detailed clinical EEG. Furthermore, a substantial literature search of the Chinese Biomedical Literature Database, PubMed, and Cochrane Central Register of Controlled Trials EMBASE was also conducted, which revealed a total of 22 reported cases between January 2008 to January 2021. We analyzed 29 cases of Alpers' syndrome caused by different gene variants, of which 22 cases were related to POLG gene mutation and 7 cases were related to PARS2, CARS2, FARS2, NARS2, and GABRB2 gene mutation, and found that patients with distinctive pathogenic variants exhibited comparable phenotypes and similar EEG patterns. And we defined EEG characteristics found specifically in Alpers' syndrome. Rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS) is a characteristic EEG finding in the early stages of Alpers' syndrome and is a kind of epileptic phenomenon, which can provide clues for the early diagnosis of the disease.

Keywords:  Alpers; POLG; RHADS; diagnosis; electroencephalogram; syndrome

DOI:  https://doi.org/10.3389/fphar.2021.669516
Metab Brain Dis. 2021 Oct 28.

Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.

Feixia Zhan, Xiaoli Liu, Ruilong Ni, Taotao Liu, Yuwen Cao, Jingying Wu, Wotu Tian, Xinghua Luan, Li Cao.

  Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 variants, one shared variant (c.286T>C) has been previously reported, the remaining two (c.189delC and c.580 A>G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.

Keywords:  IBA57; Leukoencephalopathy; MMDS; Mitochondrial disorders; Multiple mitochondrial dysfunction syndrome

DOI:  https://doi.org/10.1007/s11011-021-00856-8
Sci Rep. 2021 Oct 27. 11(1): 21207

The function of Scox in glial cells is essential for locomotive ability in Drosophila.

Ryosuke Kowada, Atsushi Kodani, Hiroyuki Ida, Masamitsu Yamaguchi, Im-Soon Lee, Yasushi Okada, Hideki Yoshida.

Synthesis of cytochrome c oxidase (Scox) is a Drosophila homolog of human SCO2 encoding a metallochaperone that transports copper to cytochrome c, and is an essential protein for the assembly of cytochrome c oxidase in the mitochondrial respiratory chain complex. SCO2 is highly conserved in a wide variety of species across prokaryotes and eukaryotes, and mutations in SCO2 are known to cause mitochondrial diseases such as fatal infantile cardioencephalomyopathy, Leigh syndrome, and Charcot-Marie-Tooth disease, a neurodegenerative disorder. These diseases have a common symptom of locomotive dysfunction. However, the mechanisms of their pathogenesis remain unknown, and no fundamental medications or therapies have been established for these diseases. In this study, we demonstrated that the glial cell-specific knockdown of Scox perturbs the mitochondrial morphology and function, and locomotive behavior in Drosophila. In addition, the morphology and function of synapses were impaired in the glial cell-specific Scox knockdown. Furthermore, Scox knockdown in ensheathing glia, one type of glial cell in Drosophila, resulted in larval and adult locomotive dysfunction. This study suggests that the impairment of Scox in glial cells in the Drosophila CNS mimics the pathological phenotypes observed by mutations in the SCO2 gene in humans.

DOI: https://doi.org/10.1038/s41598-021-00663-2
Pol J Pathol. 2021 ;pii: 45313. [Epub ahead of print]72(2): 185-189

Adult-onset, isolated respiratory chain complex-IV deficiency with mild manifestations.

Josef Finsterer, Michael Winklehner.

  Isolated respiratory chain complex-IV deficiency (ICIVD) usually manifests clinically as an early-onset, severe, multisystem mitochondrial disorder (MID) and only rarely with mild manifestations. Here we present an adult patient with late onset ICIVD with slowly progressive, mild clinical manifestations. In a 57-years old Caucasian male with exercise-induced myalgia, muscle cramps, ptosis, and recurrent creatine-kinase (CK) elevation, muscle biopsy and biochemical investigations of the left lateral vastus muscle revealed ICIVD. He additionally had developed diabetes, arterial hypertension, hyperlipidemia, retinal detachment, transient hypothyroidism, and a hearing fall. The family history was positive for diabetes, Parkinsonism, and dementia in the mother and myopathy in the brother, suggesting maternal transmission of the MID. Conclusions: ICIVD may manifest in adulthood with only mild manifestations and may take a slowly progressive course. Patients with mild hyper-CKemia and mild multisystem manifestations, including the muscle, profit from muscle biopsy and biochemical investigations.

Keywords:   mitochondrial; multisystem; myopathy.; respiratory chain; mtDNA

DOI:  https://doi.org/10.5114/pjp.2021.109523
FEBS J. 2021 Oct 24.

Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and subsequent mitochondrial accumulation in human fibroblasts.

Yasuhiro Takenaka, Ikuo Inoue, Takanari Nakano, Masaaki Ikeda, Yoshihiko Kakinuma.

  Proteolytic activity declines with age, resulting in the accumulation of aggregated proteins in aged organisms. To investigate how disturbance in proteostasis causes cellular senescence, we developed a stress-induced premature senescence (SIPS) model, in which normal human fibroblast MRC-5 cells were treated with the proteasome inhibitor MG132 or the V-ATPase inhibitor bafilomycin A1 (BAFA1) for 5 days. Time-course studies revealed a significant increase in intracellular reactive oxygen species (ROS) and mitochondrial superoxide during and after drug treatment. Mitochondrial membrane potential initially decreased, suggesting temporal mitochondrial dysfunction during drug treatment, but was restored along with mitochondrial accumulation after drug treatment. AMP-activated protein kinase alpha (AMPKα) was notably activated during treatment; thereafter, intracellular ATP levels significantly increased. SIPS induction by MG132 or BAFA1 was partially attenuated by co-treatment with vitamin E or rapamycin, in which the levels of ROS, mitochondrial accumulation, and protein aggregates were suppressed, implying the critical involvement of oxidative stress and mitochondrial function in SIPS progression. Rapamycin co-treatment also augmented the expression of HSP70 and activation of AKT, which could recover proteostasis and promote cell survival, respectively. Our study proposes a possible pathway from the disturbed proteostasis to cellular senescence via excess ROS production as well as functional and quantitative changes in mitochondria.

Keywords:  DNA damage response; aggregate; lysosome; oxidative stress; proteasome

DOI:  https://doi.org/10.1111/febs.16249
Int J Biochem Cell Biol. 2021 Oct 22. pii: S1357-2725(21)00182-5. [Epub ahead of print] 106101

It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.

Irene M G M Hemel, Rita Sarantidou, Mike Gerards.

  Mitochondria change their shape, size and number, in response to cellular demand, through mitochondrial dynamics. The interaction between mitochondria and the ER, through ER-mitochondrial contact sites, is crucial in mitochondrial dynamics. Several protein complexes tethering mitochondria to the ER include proteins involved in fission or fusion but also proteins involved in calcium homeostasis, which is known to affect mitochondrial dynamics. The formation of these contact sites are especially important for mitochondrial fission as these contact sites induce both outer and inner membrane constriction, prior to recruitment of Drp1. While the exact molecular mechanisms behind these constrictions remain uncertain, several hypotheses have been proposed. In this review, we discuss the involvement of tethering complexes in mitochondrial dynamics and provide an overview of the current knowledge and hypotheses on the constriction of the outer and inner mitochondrial membrane at ER-mitochondrial contact sites.

Keywords:  ER-mitochondrial contact; Mitochondrial dynamics; Mitochondrial membrane constriction

DOI:  https://doi.org/10.1016/j.biocel.2021.106101
Neurology. 2021 Oct 29. pii: 10.1212/WNL.0000000000013015. [Epub ahead of print]

Migratory Rolandic Encephalopathy Caused by the Mitochondrial ND3 Mutation.

Department of Neurology, Qilu Hospital, Shandong University

DOI: https://doi.org/10.1212/WNL.0000000000013015
Am J Hum Genet. 2021 Oct 25. pii: S0002-9297(21)00379-7. [Epub ahead of print]

Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations.

Genomics England Research Consortium

  Human mitochondrial RNase P (mt-RNase P) is responsible for 5' end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.

Keywords:  MRPP3; PRORP; Perrault syndrome; RNase P; leukodystrophy; mitochondria; primary ovarian insufficiency; rare disease; sensorineural hearing loss

DOI:  https://doi.org/10.1016/j.ajhg.2021.10.002
Front Cell Dev Biol. 2021 ;9 710247

Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3.

Matthew J Jennings, Denisa Hathazi, Chi D L Nguyen, Benjamin Munro, Ute Münchberg, Robert Ahrends, Annette Schenck, Ilse Eidhof, Erik Freier, Matthis Synofzik, Rita Horvath, Andreas Roos.

  Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.

Keywords:  DNAJC3; cholesterol-stress; mitochondria; proteomics; unfolded protein response (UPR)

DOI:  https://doi.org/10.3389/fcell.2021.710247
Exerc Sport Sci Rev. 2021 Oct 22.

The HO-1/CO System and Mitochondrial Quality Control in Skeletal Muscle.

Heath G Gasier, Hagir B Suliman, Claude A Piantadosi.

ABSTRACT: Inducible heme oxygenase (HO)-1 catalyzes the breakdown of heme to biliverdin, iron and carbon monoxide (CO). CO binds to cytochrome c oxidase and alters mitochondrial redox balance and coordinately regulates mitochondrial quality control (MQC) during oxidant stress and inflammation. The hypothesis presented is that skeletal muscle HO-1/CO system helps modulate components in the MQC cycle during metabolic stress.

DOI: https://doi.org/10.1249/JES.0000000000000277
Am J Clin Pathol. 2021 Oct 26. pii: aqab174. [Epub ahead of print]

Determining Mitochondrial 3243A>G Heteroplasmy Using an ARMS-ddPCR Strategy.

Pu Xu, Manli Jia, Jimei Yan, Xiangshu Yuan, Weidong Yu, Zhuohua Zhou, Hezhi Fang, Feng Gao, Lijun Shen.

  OBJECTIVES: Determining mitochondrial DNA (mtDNA) A-to-G substitution at nucleotide 3243 (m.3243A>G) heteroplasmy is essential for both precision diagnosis of m.3243A>G-associated mitochondrial disease and genetic counseling. Precise determination of m.3243A>G heteroplasmy is challenging, however, without appropriate strategies to accommodate heteroplasmic levels ranging from 1% to 100% in samples carrying thousands to millions of mtDNA copies.METHODS: We used a combined strategy of amplification-refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) and droplet digital PCR (ddPCR) to determine m.3243A>G heteroplasmy. Primers were specifically designed and screened for both ARMS-qPCR and ddPCR to determine m.3243A>G heteroplasmy. An optimized ARMS-qPCR-ddPCR-based strategy was established using artificial standards, with different mixtures of m.3243A-containing and m.3243G-containing plasmids and further tested using clinical samples containing the m.3243A>G mutation.
RESULTS: One of 20 primer pairs designed in the study was omitted for ARMS-qPCR-ddPCR strategy application according to criteria of 85% to 110%, R2 > 0.98 amplification efficiency, melt curve with a single clear peak, and specificity for m.3243A and m.3243G artificial standards (|CtWt-CtMut|max). Using plasmid standards with various m.3243A>G heteroplasmy (1%-100%) at low, mid, and high copy numbers (3,000, 104, and 105-107, respectively) and DNA from the blood of 20 patients carrying m.3243A>G with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, we found that ARMS-qPCR was reliable for determining m.3243A>G at 3% to 100% for low copy number and 1% to 100% for mid to high copy number samples. Meanwhile, ddPCR was reliable for determining m.3243A>G at 1% to 100% at low to mid copy number samples.
CONCLUSIONS: An ARMS-qPCR-ddPCR-based strategy was successfully established for precise determination of m.3243A>G heteroplasmy in complex clinical samples.

Keywords:  ARMS-qPCR; Heteroplasmy; Mitochondrial disease; ddPCR; mtDNA copy number

DOI:  https://doi.org/10.1093/ajcp/aqab174
Front Mol Biosci. 2021 ;8 717328

Players in Mitochondrial Dynamics and Female Reproduction.

Weiwei Zou, Dongmei Ji, Zhiguo Zhang, Li Yang, Yunxia Cao.

  Mitochondrial dynamics (fission and fusion) are essential physiological processes for mitochondrial metabolic function, mitochondrial redistribution, and mitochondrial quality control. Various proteins are involved in regulating mitochondrial dynamics. Aberrant expression of these proteins interferes with mitochondrial dynamics and induces a range of diseases. Multiple therapeutic approaches have been developed to treat the related diseases in recent years, but their curative effects are limited. Meanwhile, the role of mitochondrial dynamics in female reproductive function has attracted progressively more attention, including oocyte development and maturation, fertilization, and embryonic development. Here, we reviewed the significance of mitochondrial dynamics, proteins involved in mitochondrial dynamics, and disorders resulting from primary mitochondrial dynamic dysfunction. We summarized the latest therapeutic approaches of hereditary mitochondrial fusion-fission abnormalities and reviewed the recent advances in female reproductive mitochondrial dynamics.

Keywords:  diseases; mitochondrial dynamics; protein; reproduction; therapy

DOI:  https://doi.org/10.3389/fmolb.2021.717328
Nat Metab. 2021 Oct 25.

Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2.

Karthickeyan Chella Krishnan, Laurent Vergnes, Rebeca Acín-Pérez, Linsey Stiles, Michael Shum, Lijiang Ma, Etienne Mouisel, Calvin Pan, Timothy M Moore, Miklós Péterfy, Casey E Romanoski, Karen Reue, Johan L M Björkegren, Markku Laakso, Marc Liesa, Aldons J Lusis.

We have previously suggested a central role for mitochondria in the observed sex differences in metabolic traits. However, the mechanisms by which sex differences affect adipose mitochondrial function and metabolic syndrome are unclear. Here we show that in both mice and humans, adipose mitochondrial functions are elevated in females and are strongly associated with adiposity, insulin resistance and plasma lipids. Using a panel of diverse inbred strains of mice, we identify a genetic locus on mouse chromosome 17 that controls mitochondrial mass and function in adipose tissue in a sex- and tissue-specific manner. This locus contains Ndufv2 and regulates the expression of at least 89 mitochondrial genes in females, including oxidative phosphorylation genes and those related to mitochondrial DNA content. Overexpression studies indicate that Ndufv2 mediates these effects by regulating supercomplex assembly and elevating mitochondrial reactive oxygen species production, which generates a signal that increases mitochondrial biogenesis.

DOI: https://doi.org/10.1038/s42255-021-00481-w
J Inherit Metab Dis. 2021 Oct 29.

Current and Future Treatment Approaches for Barth Syndrome.

Reid Thompson, John Jefferies, Suya Wang, William T Pu, Clifford Takemoto, Brittany Hornby, Andrea Heyman, Michael T Chin, Hilary Vernon.

  Barth Syndrome is an X-linked disorder of mitochondrial cardiolipin metabolism caused by pathogenic variants in TAFAZZIN with pleiotropic effects including cardiomyopathy, neutropenia, growth delay, and skeletal myopathy. Management requires a multidisciplinary approach to the organ-specific manifestations including specialists from cardiology, hematology, nutrition, physical therapy, genetics, and metabolism. Currently, treatment is centered on management of specific clinical features, and is not targeted towards remediating the underlying biochemical defect. However, two clinical trials have been recently undertaken which target the mitochondrial pathology of this disease: a study to examine the effects of elamipretide, a cardiolipin targeted agent, and a study to examine the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist. Treatments to directly target the defective TAFAZZIN pathway are under development, including enzyme and gene therapies. This article is protected by copyright. All rights reserved.

Keywords:  Barth Syndrome; Cardiolipin; Cardiomyopathy; TAFAZZIN

DOI:  https://doi.org/10.1002/jimd.12453
Antioxid Redox Signal. 2021 Oct 29.

The many roles mitochondria play in mammalian aging.

Caio M P F Batalha, Anibal Eugênio Vercesi, Nadja C Souza-Pinto.

SIGNIFICANCE: Aging is a natural process that affects most living organisms, resulting in increased mortality. As the world population ages, the prevalence of age-associated diseases, and their associated healthcare costs, has increased sharply. A better understanding of the molecular mechanisms that lead to cellular dysfunction may provide important targets for interventions to prevent or treat these diseases. Recent Advances: Although the mitochondrial theory of aging has been proposed over 40 years ago, recent new data has given stronger support for a central role for mitochondrial dysfunction in several pathways that are deregulated during normal aging and age-associated disease.CRITICAL ISSUES: Several of the experimental evidence linking mitochondrial alterations to age-associated loss of function are correlative and mechanistic insight are still elusive. Here, we review how mitochondrial dysfunction may be involved in many of the known hallmarks of aging, and how these pathways interact in an intricate net of molecular relationships.
FUTURE DIRECTIONS: As it has become clear that mitochondrial dysfunction plays causative roles in normal aging and age-associated diseases, it is necessary to better define the molecular interactions and the temporal and causal relations between these changes and the relevant phenotypes seen during the aging process.

DOI: https://doi.org/10.1089/ars.2021.0074
Neuromuscul Disord. 2021 Sep 06. pii: S0960-8966(21)00620-9. [Epub ahead of print]

MuSK not MNGIE: Atypical MuSK-antibody myasthenia presenting as a genetic disorder.

Simon Thebault, Ebrima Gibbs, Pierre Bourque, Doug McKim, Kawan Rakhra, Ari Breiner, Hans Frykman, Jodi Warman-Chardon.

  Myasthenia gravis is a treatable autoimmune disease caused by autoantibodies directed against membrane proteins at the neuromuscular junction. While acetylcholine receptor antibodies are most common, a minority of patients have antibodies directed against muscle-specific kinase (MuSK-antibody). Differentiating features often include subacute onset and rapid progression of bulbar, respiratory and neck extensor muscles, with sparing of distal appendicular muscles, most commonly in middle-aged females. Here we present an atypical presentation of MuSK-antibody myasthenic syndrome in a young male consisting of a gradual-onset, insidiously-progressive, non-fatigable and non-fluctuating ocular, bulbar and oesophageal weakness, with a normal frontalis single fibre EMG. This case clinically resembled a mitochondrial myopathy (Mitochondrial Neurogastrointestinal Encephalopathy-MNGIE) with a poor prognosis. Because of the atypical presentation, MuSK antibodies were identified very late in the disease course, at which point the patient responded very well to immunotherapy. We report an unusual presentation of an uncommon but treatable condition, illustrating significant phenotypic heterogeneity possible in MuSK-antibody myasthenic syndrome.

Keywords:  Autoimmune diseases; EMG; Mitochondrial disorders; MuSK; Muscle disease; Myasthenia

DOI:  https://doi.org/10.1016/j.nmd.2021.08.014
Front Neurol. 2021 ;12 694966

Charcot-Marie-Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy.

Yuqing Guan, Yanxia Zhang, Xin-Ming Shen, Liang Zhou, Xuan Shang, Yu Peng, Yafang Hu, Wei Li.

  A 29-year-old female experienced chronic progressive peripheral neuropathy since childhood and was diagnosed with Charcot-Marie-Tooth disease (CMT) at age 15. She developed recurrent, fever-induced rhabdomyolysis (RM) at age 24. EMG studies showed decreased amplitude of compound muscle action potential, declined motor conductive velocity, and absence of sensor nerve action potential. Acylcarnitine analysis revealed elevated C16-OH, C18-OH, and C18:1-OH. Muscle biopsy showed scattered foci of necrotic myofibers invaded by macrophages, occasional regenerating fibers, and remarkable muscle fiber type grouping. Whole-exome sequencing identified two novel heterozygous mutations: c.490G>A (p.G164S) and c.686G>A (p.R229Q) in HADHB gene encoding the β-subunit of mitochondrial trifunctional protein (MTP). Reduction of long-chain fatty acid via dietary restrictions alleviated symptoms effectively. Our study indicates that the defect of the MTP β-subunit accounts for both CMT and RM in the same patient and expands the clinical spectrum of disorders caused by the HADHB mutations. Our systematic review of all MTPD patients with dietary treatment indicates that the effect of dietary treatment is related to the age of onset and the severity of symptoms.

Keywords:  Charcot-Marie-Tooth disease; HADHB; mitochondrial trifunctional protein deficiency; peripheral neuropathy; rhabdomyolysis

DOI:  https://doi.org/10.3389/fneur.2021.694966
J Dev Biol. 2021 Sep 22. pii: 39. [Epub ahead of print]9(4):

Quantitative Craniofacial Analysis and Generation of Human Induced Pluripotent Stem Cells for Muenke Syndrome: A Case Report.

Fahad K Kidwai, Byron W H Mui, Konstantinia Almpani, Priyam Jani, Cyrus Keyvanfar, Kulsum Iqbal, Sriram S Paravastu, Deepika Arora, Pamela Orzechowski, Randall K Merling, Barbara Mallon, Vamsee D Myneni, Moaz Ahmad, Paul Kruszka, Maximilian Muenke, Jeremiah Woodcock, Jeffrey W Gilman, Pamela G Robey, Janice S Lee.

  In this case report, we focus on Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in fibroblast growth factor receptor 3 (FGFR3) and characterized by uni- or bilateral coronal suture synostosis, macrocephaly without craniosynostosis, dysmorphic craniofacial features, and dental malocclusion. The clinical findings of MS are further complicated by variable expression of phenotypic traits and incomplete penetrance. As such, unraveling the mechanisms behind MS will require a comprehensive and systematic way of phenotyping patients to precisely identify the impact of the mutation variant on craniofacial development. To establish this framework, we quantitatively delineated the craniofacial phenotype of an individual with MS and compared this to his unaffected parents using three-dimensional cephalometric analysis of cone beam computed tomography scans and geometric morphometric analysis, in addition to an extensive clinical evaluation. Secondly, given the utility of human induced pluripotent stem cells (hiPSCs) as a patient-specific investigative tool, we also generated the first hiPSCs derived from a family trio, the proband and his unaffected parents as controls, with detailed characterization of all cell lines. This report provides a starting point for evaluating the mechanistic underpinning of the craniofacial development in MS with the goal of linking specific clinical manifestations to molecular insights gained from hiPSC-based disease modeling.

Keywords:  Muenke syndrome; craniofacial abnormalities; craniosynostosis; geometric morphometric analysis; human induced pluripotent stem cells

DOI:  https://doi.org/10.3390/jdb9040039
Front Genome Ed. 2021 ;3 630600

Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies.

Amy McTague, Giada Rossignoli, Arianna Ferrini, Serena Barral, Manju A Kurian.

  Therapeutic advances for neurological disorders are challenging due to limited accessibility of the human central nervous system and incomplete understanding of disease mechanisms. Many neurological diseases lack precision treatments, leading to significant disease burden and poor outcome for affected patients. Induced pluripotent stem cell (iPSC) technology provides human neuronal cells that facilitate disease modeling and development of therapies. The use of genome editing, in particular CRISPR-Cas9 technology, has extended the potential of iPSCs, generating new models for a number of disorders, including Alzheimers and Parkinson Disease. Editing of iPSCs, in particular with CRISPR-Cas9, allows generation of isogenic pairs, which differ only in the disease-causing mutation and share the same genetic background, for assessment of phenotypic differences and downstream effects. Moreover, genome-wide CRISPR screens allow high-throughput interrogation for genetic modifiers in neuronal phenotypes, leading to discovery of novel pathways, and identification of new therapeutic targets. CRISPR-Cas9 has now evolved beyond altering gene expression. Indeed, fusion of a defective Cas9 (dCas9) nuclease with transcriptional repressors or activation domains allows down-regulation or activation of gene expression (CRISPR interference, CRISPRi; CRISPR activation, CRISPRa). These new tools will improve disease modeling and facilitate CRISPR and cell-based therapies, as seen for epilepsy and Duchenne muscular dystrophy. Genome engineering holds huge promise for the future understanding and treatment of neurological disorders, but there are numerous barriers to overcome. The synergy of iPSC-based model systems and gene editing will play a vital role in the route to precision medicine and the clinical translation of genome editing-based therapies.

Keywords:  CRISPR; CRISPRa; CRISPRi; disease modeling; gene editing; induced pluripotent stem cells; neurological disorders; precision treatment

DOI:  https://doi.org/10.3389/fgeed.2021.630600
Autophagy. 2021 Oct 25. 1-18

Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice.

Palak Ahuja, Chun Fai Ng, Brian Pak Shing Pang, Wing Suen Chan, Margaret Chui Ling Tse, Xinyi Bi, Hiu-Lam Rachel Kwan, Daniel Brobst, Oana Herlea-Pana, Xiuying Yang, Guanhua Du, Suchaorn Saengnipanthkul, Hye Lim Noh, Baowei Jiao, Jason K Kim, Chi Wai Lee, Keqiang Ye, Chi Bun Chan.

  Mitochondrial remodeling is dysregulated in metabolic diseases but the underlying mechanism is not fully understood. We report here that BDNF (brain derived neurotrophic factor) provokes mitochondrial fission and clearance in skeletal muscle via the PRKAA/AMPK-PINK1-PRKN/Parkin and PRKAA-DNM1L/DRP1-MFF pathways. Depleting Bdnf expression in myotubes reduced fatty acid-induced mitofission and mitophagy, which was associated with mitochondrial elongation and impaired lipid handling. Muscle-specific bdnf knockout (MBKO) mice displayed defective mitofission and mitophagy, and accumulation of dysfunctional mitochondria in the muscle when they were fed with a high-fat diet (HFD). These animals also have exacerbated body weight gain, increased intramyocellular lipid deposition, reduced energy expenditure, poor metabolic flexibility, and more insulin resistance. In contrast, consuming a BDNF mimetic (7,8-dihydroxyflavone) increased mitochondrial content, and enhanced mitofission and mitophagy in the skeletal muscles. Hence, BDNF is an essential myokine to maintain mitochondrial quality and function, and its repression in obesity might contribute to impaired metabolism.Abbreviation: 7,8-DHF: 7,8-dihydroxyflavone; ACACA/ACC: acetyl Coenzyme A carboxylase alpha; ACAD: acyl-Coenzyme A dehydrogenase family; ACADVL: acyl-Coenzyme A dehydrogenase, very long chain; ACOT: acyl-CoA thioesterase; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; BDNF: brain derived neurotrophic factor; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCL2/MCP-1: chemokine (C-C motif) ligand 2; CCL5: chemokine (C-C motif) ligand 5; CNS: central nervous system; CPT1B: carnitine palmitoyltransferase 1b, muscle; Cpt2: carnitine palmitoyltransferase 2; CREB: cAMP responsive element binding protein; DNM1L/DRP1: dynamin 1-like; E2: estrogen; EHHADH: enoyl-CoenzymeA hydratase/3-hydroxyacyl CoenzymeA dehydrogenase; ESR1/ER-alpha: estrogen receptor 1 (alpha); FA: fatty acid; FAO: fatty acid oxidation; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FFA: free fatty acids; FGF21: fibroblast growth factor 21; FUNDC1: FUN14 domain containing 1; HADHA: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; HFD: high-fat diet; iWAT: inguinal white adipose tissues; MAP1LC3A/LC3A: microtubule-associated protein 1 light chain 3 alpha; MBKO; muscle-specific bdnf knockout; IL6/IL-6: interleukin 6; MCEE: methylmalonyl CoA epimerase; MFF: mitochondrial fission factor; NTRK2/TRKB: neurotrophic tyrosine kinase, receptor, type 2; OPTN: optineurin; PA: palmitic acid; PARL: presenilin associated, rhomboid-like; PDH: pyruvate dehydrogenase; PINK1: PTEN induced putative kinase 1; PPARGC1A/PGC-1α: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PRKAA/AMPK: protein kinase, AMP-activated, alpha 2 catalytic subunit; ROS: reactive oxygen species; TBK1: TANK-binding kinase 1; TG: triacylglycerides; TNF/TNFα: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1.

Keywords:  BDNF; mitochondria; mitophagy; muscle; obesity

DOI:  https://doi.org/10.1080/15548627.2021.1985257
Sci Rep. 2021 Oct 26. 11(1): 21048

A subpopulation of arenavirus nucleoprotein localizes to mitochondria.

Francesca Baggio, Udo Hetzel, Lisbeth Nufer, Anja Kipar, Jussi Hepojoki.

Viruses need cells for their replication and, therefore, ways to hijack cellular functions. Mitochondria play fundamental roles within the cell in metabolism, immunity and regulation of homeostasis due to which some viruses aim to alter mitochondrial functions. Herein we show that the nucleoprotein (NP) of arenaviruses enters the mitochondria of infected cells, affecting the mitochondrial morphology. Reptarenaviruses cause boid inclusion body disease (BIBD) that is characterized, especially in boas, by the formation of cytoplasmic inclusion bodies (IBs) comprising reptarenavirus NP within the infected cells. We initiated this study after observing electron-dense material reminiscent of IBs within the mitochondria of reptarenavirus infected boid cell cultures in an ultrastructural study. We employed immuno-electron microscopy to confirm that the mitochondrial inclusions indeed contain reptarenavirus NP. Mutations to a putative N-terminal mitochondrial targeting signal (MTS), identified via software predictions in both mamm- and reptarenavirus NPs, did not affect the mitochondrial localization of NP, suggesting that it occurs independently of MTS. In support of MTS-independent translocation, we did not detect cleavage of the putative MTSs of arenavirus NPs in reptilian or mammalian cells. Furthermore, in vitro translated NPs could not enter isolated mitochondria, suggesting that the translocation requires cellular factors or conditions. Our findings suggest that MTS-independent mitochondrial translocation of NP is a shared feature among arenaviruses. We speculate that by targeting the mitochondria arenaviruses aim to alter mitochondrial metabolism and homeostasis or affect the cellular defense.

DOI: https://doi.org/10.1038/s41598-021-99887-5
Oxid Med Cell Longev. 2021 ;2021 9932442

The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis.

Kamil Siekacz, Wojciech J Piotrowski, Mikołaj A Iwański, Paweł Górski, Adam J Białas.

Idiopathic pulmonary fibrosis (IPF) is a condition which affects mainly older adults, that suggests mitochondrial dysfunction and oxidative stress, which follow cells senescence, and might contribute to the disease onset. We have assumed pathogenesis associated with crosstalk between the extracellular matrix (ECM) and mitochondria, mainly based on mitochondrial equilibrium impairment consisting of (1) tyrosine kinases and serine-threonine kinase (TKs and ST-Ks) activation via cytokines, (2) mitochondrial electron transport chain dysfunction and in consequence electrons leak with lower ATP synthesis, (3) the activation of latent TGF-β via αVβ6 integrin, (4) tensions transduction via α2β1 integrin, (5) inefficient mitophagy, and (6) stress inhibited biogenesis. Mitochondria dysfunction influences ECM composition and vice versa. Damaged mitochondria release mitochondrial reactive oxygen species (mtROS) and the mitochondrial DNA (mtDNA) to the microenvironment. Therefore, airway epithelial cells (AECs) undergo transition and secrete cytokines. Described factors initiate an inflammatory process with immunological enhancement. In consequence, local fibroblasts exposed to harmful conditions transform into myofibroblasts, produce ECM, and induce progression of fibrosis. In our review, we summarize numerous aspects of mitochondrial pathobiology, which seem to be involved in the pathogenesis of lung fibrosis. In addition, an increasing body of evidence suggests considering crosstalk between the ECM and mitochondria in this context. Moreover, mitochondria and ECM seem to be important players in the antifibrotic treatment of IPF.

DOI: https://doi.org/10.1155/2021/9932442
Front Pharmacol. 2021 ;12 735165

Trimetazidine Modulates Mitochondrial Redox Status and Disrupted Glutamate Homeostasis in a Rat Model of Epilepsy.

Muhammad Y Al-Shorbagy, Walaa Wadie, Dalia M El-Tanbouly.

  Mitochondrial oxidative status exerts an important role in modulating glia-neuron interplay during epileptogenesis. Trimetazidine (TMZ), a well-known anti-ischemic drug, has shown promising potential against a wide range of neurodegenerative disorders including epilepsy. Nevertheless, the exact mechanistic rationale behind its anti-seizure potential has not been fully elucidated yet. Herein, the impact of TMZ against mitochondrial oxidative damage as well as glutamate homeostasis disruption in the hippocampus has been investigated in rats with lithium/pilocarpine (Li/PIL) seizures. Animals received 3 mEq/kg i.p. LiCl3 followed by PIL (single i.p.; 150 mg/kg) 20 h later for induction of seizures with or without TMZ pretreatment (25 mg/kg; i.p.) for five consecutive days. Seizure score and seizure latency were observed. Mitochondrial redox status as well as ATP and uncoupling protein 2 was recorded. Moreover, glutamate homeostasis was unveiled. The present findings demonstrate the TMZ-attenuated Li/PIL seizure score and latency. It improved mitochondrial redox status, preserved energy production mechanisms, and decreased reactive astrocytes evidenced as decreased glial fibrillary acidic protein immune-stained areas in hippocampal tissue. In addition, it modulated phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and p-AMP-activated protein kinase (p-AMPK) signaling pathways to reflect a verified anti-apoptotic effect. Consequently, it upregulated mRNA expression of astroglial glutamate transporters and reduced the elevated glutamate level. The current study demonstrates that TMZ exhibits robust anti-seizure and neuroprotective potentials. These effects are associated with its ability to modulate mitochondrial redox status, boost p-ERK1/2 and p-AMPK signaling pathways, and restore glutamate homeostasis in hippocampus.

Keywords:  ERK1/2; astrogliosis; glutamate transporters; mitochondrial oxidative stress; trimetazidine

DOI:  https://doi.org/10.3389/fphar.2021.735165
Physiol Rev. 2021 10 26.

Mitochondrial calcium exchange in physiology and disease.

Joanne F Garbincius, John W Elrod.

  The uptake of calcium into and extrusion of calcium from the mitochondrial matrix is a fundamental biological process that has critical effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium (mCa2+) cycling is implicated in numerous acquired diseases such as heart failure, stroke, neurodegeneration, diabetes, and cancer, and is genetically linked to several inherited neuromuscular disorders. Understanding the mechanisms responsible for mCa2+ exchange therefore holds great promise for the treatment of these diseases. The past decade has seen the genetic identification of many of the key proteins that mediate mitochondrial calcium uptake and efflux. Here, we present an overview of the phenomenon of mCa2+ transport, and a comprehensive examination of the molecular machinery that mediates calcium flux across the inner mitochondrial membrane: the mitochondrial uniporter complex (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB, and MCUR1), NCLX, LETM1, the mitochondrial ryanodine receptor, and the mitochondrial permeability transition pore. We then consider the physiological implications of mCa2+ flux and evaluate how alterations in mCa2+ homeostasis contribute to human disease. This review concludes by highlighting opportunities and challenges for therapeutic intervention in pathologies characterized by aberrant mCa2+ handling and by summarizing critical unanswered questions regarding the biology of mCa2+ flux.

Keywords:  calcium; energetics; metabolism; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1152/physrev.00041.2020