bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–02–06
twenty papers selected by
Catalina Vasilescu, University of Helsinki
  1. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies.
  2. Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
  3. Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
  4. The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.
  5. The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice.
  6. Mitochondrial DNA Homeostasis Impairment and Dopaminergic Dysfunction: A Trembling Balance.
  7. Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.
  8. Leigh syndrome: a study of 209 patients at the Beijing Children's Hospital.
  9. Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.
  10. Mutation Profile of Neurodegenerative Mitochondriopathy - LHON in Southern India.
  11. Diagnosis and Clinical Management of Long-chain Fatty-acid Oxidation Disorders: A Review.
  12. A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.
  13. Mitochondrial respiratory chain dysfunction alters ER sterol sensing and mevalonate pathway activity.
  14. The importance of mitochondrial quality control for maintaining skeletal muscle function across healthspan.
  15. mtDNA mutations help support cancer cells.
  16. TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.
  17. Identification of a novel homozygous SCO2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.
  18. Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains.
  19. Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
  20. Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
  1. J Neuromuscul Dis. 2022 Jan 28.
    Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies.
    Andres Berardo, Kristin Engelstad, Michio Hirano.
      Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: <  2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.
    Keywords:  DNA; Mitochondrial myopathies; deoxycytidine; mitochondrial; mitochondrial diseases; thymidine
    DOI:  https://doi.org/10.3233/JND-210786
  2. Biol Chem. 2022 Jan 31.
    Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
    Nupur Sharma, Christof Osman.
      The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.
    Keywords:  MBA1; MDM38; OXA1; RRM; Walker motifs; mitoribosome
    DOI:  https://doi.org/10.1515/hsz-2021-0398
  3. Nat Commun. 2022 Feb 03. 13(1): 651
    Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
    Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.
      Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
    DOI:  https://doi.org/10.1038/s41467-022-28272-1
  4. Mol Cell. 2022 Jan 28. pii: S1097-2765(22)00008-9. [Epub ahead of print]
    The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.
    Katia Cosentino, Vanessa Hertlein, Andreas Jenner, Timo Dellmann, Milos Gojkovic, Aida Peña-Blanco, Shashank Dadsena, Noel Wajngarten, John S H Danial, Jervis Vermal Thevathasan, Markus Mund, Jonas Ries, Ana J Garcia-Saez.
      BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble the apoptotic pore remains obscure. Here, we report that BAX and BAK present distinct oligomerization properties, with BAK organizing into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers that continue to grow during apoptosis. As a result, BAX and BAK regulate each other as they co-assemble into the same apoptotic pores, which we visualize. The relative availability of BAX and BAK molecules thereby determines the growth rate of the apoptotic pore and the relative kinetics by which mitochondrial contents, most notably mtDNA, are released. This feature of BAX and BAK results in distinct activation kinetics of the cGAS/STING pathway with implications for mtDNA-mediated paracrine inflammatory signaling.
    Keywords:  AFM; BAK; BAX; BCL-2; inflammatory cell death; membrane pore; mitochondria; pore-forming protein; single-molecule imaging; super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.molcel.2022.01.008
  5. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2120476119. [Epub ahead of print]119(6):
    The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice.
    Catherine A Makarewich, Amir Z Munir, Svetlana Bezprozvannaya, Aaron M Gibson, Soo Young Kim, Misty S Martin-Sandoval, Thomas P Mathews, Luke I Szweda, Rhonda Bassel-Duby, Eric N Olson.
      Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small size. To search for cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contributed to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function.
    Keywords:  cardiac; microprotein; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2120476119
  6. Ageing Res Rev. 2022 Jan 31. pii: S1568-1637(22)00020-4. [Epub ahead of print] 101578
    Mitochondrial DNA Homeostasis Impairment and Dopaminergic Dysfunction: A Trembling Balance.
    Arianna Manini, Elena Abati, Giacomo Pietro Comi, Stefania Corti, Dario Ronchi.
      Maintenance of mitochondrial DNA (mtDNA) homeostasis includes a variety of processes, such as mtDNA replication, repair, and nucleotides synthesis, aimed at preserving the structural and functional integrity of mtDNA molecules. Mutations in several nuclear genes (i.e., POLG, POLG2, TWNK, OPA1, DGUOK, MPV17, TYMP) impair mtDNA maintenance, leading to clinical syndromes characterized by mtDNA depletion and/or deletions in affected tissues. In the past decades, studies have demonstrated a progressive accumulation of multiple mtDNA deletions in dopaminergic neurons of the substantia nigra in elderly population and, to a greater extent, in Parkinson's disease patients. Moreover, parkinsonism has been frequently described as a prominent clinical feature in mtDNA instability syndromes. Among Parkinson's disease-related genes with a significant role in mitochondrial biology, PARK2 and LRRK2 specifically take part in mtDNA maintenance. Moreover, a variety of murine models (i.e., "Mutator", "MitoPark", "PD-mitoPstI", "Deletor", "Twinkle-dup" and "TwinkPark") provided in vivo evidence that mtDNA stability is required to preserve nigrostriatal integrity. Here, we review and discuss the clinical, genetic, and pathological background underlining the link between impaired mtDNA homeostasis and dopaminergic degeneration.
    Keywords:  POLG1, Twinkle; Parkinsonism; Parkinson’s disease; mitochondrion; mtDNA homeostasis
    DOI:  https://doi.org/10.1016/j.arr.2022.101578
  7. Genetics. 2022 Jan 20. pii: iyac007. [Epub ahead of print]
    Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.
    Anna M Kabala, Krishia Binko, François Godard, Camille Charles, Alain Dautant, Emilia Baranowska, Natalia Skoczen, Kewin Gombeau, Marine Bouhier, Hubert D Becker, Sharon H Ackerman, Lars M Steinmetz, Déborah Tribouillard-Tanvier, Rosa Kucharczyk, Jean-Paul di Rago.
      The yeast mitochondrial ATP synthase is an assembly of 28 subunits of 17 types of which 3 (subunits 6, 8, and 9) are encoded by mitochondrial genes while the 14 others have a nuclear genetic origin. Within the membrane domain (FO) of this enzyme, the subunit 6 and a ring of 10 identical subunits 9 transport protons across the mitochondrial inner membrane coupled to ATP synthesis in the extra-membrane structure (F1) of ATP synthase. As a result of their dual genetic origin, the ATP synthase subunits are synthesized in the cytosol and inside the mitochondrion. How they are produced in the proper stoichiometry from two different cellular compartments is still poorly understood. The experiments herein reported show that the rate of translation of the subunits 9 and 6 is enhanced in strains with mutations leading to specific defects in the assembly of these proteins. These translation modifications involve assembly intermediates interacting with subunits 6 and 9 within the final enzyme and cis-regulatory sequences that control gene expression in the organelle. In addition to enabling a balanced output of the ATP synthase subunits, these assembly-dependent feedback loops are presumably important to limit the accumulation of harmful assembly intermediates that have the potential to dissipate the mitochondrial membrane electrical potential and the main source of chemical energy of the cell.
    Keywords:  ATP synthase; Mitochondria; Mitochondria DNA; Mitochondrial biogenesis; Mitochondrial gene expression; yeast
    DOI:  https://doi.org/10.1093/genetics/iyac007
  8. Ann Neurol. 2022 Jan 30.
    Leigh syndrome: a study of 209 patients at the Beijing Children's Hospital.
    Sarah L Stenton, Ying Zou, Hua Cheng, Zhimei Liu, Junling Wang, Danmin Shen, Hong Jin, Changhong Ding, Xiaolu Tang, Suzhen Sun, Hong Han, Yanli Ma, Weihua Zhang, Ruifeng Jin, Hua Wang, Dan Sun, Jun Lan Lv, Holger Prokisch, Fang Fang.
       OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival.
    METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis.
    RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥ 90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176 T > C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993 T > C and m.9176 T > C), SURF1, and ALDH5A1 (≤50% 3 year survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year survival).
    INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counselling, and to the design and monitoring of future clinical trials, the next frontier of LS research. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ana.26313
  9. J Cell Sci. 2022 Jan 31. pii: jcs.258956. [Epub ahead of print]
    Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.
    Qiancong Zhao, Shun Yan, Jin Lu, Danitra J Parker, Huiying Wu, Qianchuang Sun, David K Crossman, Shanrun Liu, Qin Wang, Hiromi Sesaki, Kasturi Mitra, Kexiang Liu, Kai Jiao.
      Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 on cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart field-derived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the reduced cellular energy level to decreased transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first mouse genetic evidence to suggest that Drp1 is essential for RV development. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.
    Keywords:  Drp1; Heart development; RP gene transcription
    DOI:  https://doi.org/10.1242/jcs.258956
  10. Gene. 2022 Jan 29. pii: S0378-1119(22)00021-X. [Epub ahead of print] 146202
    Mutation Profile of Neurodegenerative Mitochondriopathy - LHON in Southern India.
    Poigaialwar Gowri, Ponraj Sathish, Shanmugam Mahesh Kumar, Periasamy Sundaresan.
       BACKGROUND: Leber's Hereditary Optic Neuropathy (LHON) is a rare mitochondriopathy causing retinal ganglion cell degeneration resulting in central vision loss. It is caused by mitochondrial DNA (mtDNA) mutations and thus follows maternal inheritance pattern.
    METHODS: We analysed the whole mitochondrial genome in 100 South Indian LHON patients by utilizing Sanger and Next Generation Sequencing approaches. Haplogroup analysis was performed using HaploGrep2 to predict the risk group. Methylation changes in the mtDNA D-loop region were investigated by performing methylation-specific polymerase chain reaction (MSP).
    RESULTS: LHON associated mutations were detected in 55% of the patients of which 42% harboured the primary mutations and 13% harboured potentially pathogenic variants that were previously reported to cause LHON. The candidate mutations identified with confirmed pathogenicity are: m.11778G>A (38%), m.14484T>C (3%), m.4171C>A (1%) and m.11696G>A (1%). MSP results demonstrated that the D-loop region was unmethylated in all the study subjects including mutation-positive patients, mutation-negative patients, asymptomatic carriers, and controls. Haplogroup-M was prevalent (69%) in the study cohort followed by R (14%), U (9%), N (3%), HV (2%), G (2%), and W (1%). The frequency of the predominant mutation m.11778G>A was found lower (̴ 11%) in haplogroup-U.
    CONCLUSIONS: South Indian LHON cohort shows a unique profile of mtDNA mutations and haplogroup association presumably with no role of D-loop methylation. MT-ND4, MT-ND5, and MT-ND1 serve as the hotspot genes in this cohort. The presence of LHON associated mutations in patients lacking the common primary mutations insists on the necessity of mitochondrial genome sequencing in individuals suspected with LHON.
    Keywords:  D-loop methylation; LHON; Mitochondrial genome; Phylogenetic analysis; South India; mtDNA mutations
    DOI:  https://doi.org/10.1016/j.gene.2022.146202
  11. touchREV Endocrinol. 2021 Nov;17(2): 108-111
    Diagnosis and Clinical Management of Long-chain Fatty-acid Oxidation Disorders: A Review.
    Joshua J Baker, Barbara K Burton.
      Long-chain fatty-acid oxidation disorders (LC-FAODs) are autosomal recessive inherited metabolic conditions that occur due to a disruption in the body's ability to perform mitochondrial beta oxidation. Expanded newborn screening is widening phenotypic understanding of these disorders, as well improving our knowledge of disease incidence. Management of these disorders is focused on avoidance of fasting, dietary changes and supplementation with energy sources that bypass the metabolic block. Recent US Food and Drug Administration approval of triheptanoin has improved the outcome for affected individuals. New research into dietary modifications and novel pharmacologic therapies continues for these disorders. In this article, we review the major LC-FAODs and their clinical presentation.
    Keywords:  Long-chain fatty-acid oxidation disorders (LC-FAODs); beta oxidation; inborn errors of metabolism; newborn screening; nutrition; triheptanoin
    DOI:  https://doi.org/10.17925/EE.2021.17.2.108
  12. Cell Mol Life Sci. 2022 Feb 04. 79(2): 120
    A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons.
    Noah Tjiang, Hans Zempel.
      Loss of neuronal polarity and missorting of the axonal microtubule-associated-protein TAU are hallmarks of Alzheimer's disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is unclear. The axon-initial-segment (AIS) is vital for maintaining neuronal polarity, action potential generation, and-here important-TAU-sorting. Here, we investigate the role of mitochondria in the AIS for maintenance of TAU cellular polarity. Using not only global and local mitochondria impairment via inhibitors of the respiratory chain and a locally activatable protonophore/uncoupler, but also live-cell-imaging and photoconversion methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived forebrain/cortical neurons, and assessed somatic presence of TAU. Global application of mitochondrial toxins efficiently induced tauopathy-like TAU-missorting, indicating involvement of mitochondria in TAU-polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Mechanistically, mitochondrial impairment sufficient to induce TAU-missorting results in decreases of calcium oscillation but increases in baseline calcium, yet chelating intracellular calcium did not prevent mitochondrial impairment-induced TAU-missorting. Stabilizing microtubules via taxol prevented TAU-missorting, hinting towards a role for impaired microtubule dynamics in mitochondrial-dysfunction-induced TAU-missorting. We provide evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU polarity. Mitochondrial impairment may be an upstream event in and therapeutic target for AD/tauopathy.
    Keywords:  Alzheimer's disease; Axon initial segment/AIS; Live-cell-imaging; Microtubule; Mitochondria; Mitochondriopathy; Neuron; Neuronal cell polarity; TAU; Tauopathy
    DOI:  https://doi.org/10.1007/s00018-022-04150-3
  13. J Biol Chem. 2022 Jan 28. pii: S0021-9258(22)00092-8. [Epub ahead of print] 101652
    Mitochondrial respiratory chain dysfunction alters ER sterol sensing and mevalonate pathway activity.
    Christopher Tadhg James Wall, Gregory Lefebvre, Sylviane Metairon, Patrick Descombes, Andreas Wiederkehr, Jaime Santo Domingo.
      Mitochondrial dysfunction induces a strong adaptive retrograde signaling response; however, many of the down-stream effectors of this response remain to be discovered. Here, we studied the shared transcriptional responses to three different mitochondrial respiratory chain inhibitors in human primary skin fibroblasts using QuantSeq 3'-RNA-sequencing. We found that genes involved in the mevalonate pathway were concurrently downregulated, irrespective of the respiratory chain complex affected. Targeted metabolomics demonstrated that impaired mitochondrial respiration at any of the three affected complexes also had functional consequences on the mevalonate pathway, reducing levels of cholesterol precursor metabolites. A deeper study of complex I inhibition showed a reduced activity of ER-bound sterol-sensing enzymes through impaired processing of the transcription factor SREBP2 and accelerated degradation of the ER cholesterol-sensors SQLE and HMGCR. These adaptations of mevalonate pathway activity affected neither total intracellular cholesterol levels nor the cellular free (non-esterified) cholesterol pool. Finally, measurement of intracellular cholesterol using the fluorescent cholesterol binding dye filipin revealed that complex I inhibition elevated cholesterol on intracellular compartments. Taken together, our study shows that mitochondrial respiratory chain dysfunction elevates intracellular free cholesterol levels and therefore attenuates the expression of mevalonate pathway enzymes, which lowers endogenous cholesterol biosynthesis, disrupting the metabolic output of the mevalonate pathway. We conclude that intracellular disturbances in cholesterol homeostasis may alter systemic cholesterol management in diseases associated with declining mitochondrial function.
    Keywords:  Cholesterol; CoQ; HMGCR; SQLE; SREBP2; farnesyl pyrophosphate; geranyl pyrophosphate; mevalonate pathway; mitochondria; retrograde signaling; sterol; ubiquinol
    DOI:  https://doi.org/10.1016/j.jbc.2022.101652
  14. Am J Physiol Cell Physiol. 2022 Feb 02.
    The importance of mitochondrial quality control for maintaining skeletal muscle function across healthspan.
    James Sligar, Danielle A Debruin, Nicholas J Saner, Ashleigh M Philp, Andrew Philp.
      As the principal energy-producing organelles of the cell, mitochondria support numerous biological processes related to metabolism, growth and regeneration in skeletal muscle. Deterioration in skeletal muscle functional capacity with age is thought to be driven in part by a reduction in skeletal muscle oxidative capacity and reduced fatigue resistance. Underlying this maladaptive response is the development of mitochondrial dysfunction caused by alterations in mitochondrial quality control (MQC), a term encompassing processes of mitochondrial synthesis (biogenesis), remodelling (dynamics) and degradation (mitophagy). Knowledge regarding the role and regulation of MQC in skeletal muscle and the influence of ageing in this process have rapidly advanced in the last decade. Given the emerging link between ageing and MQC, therapeutic approaches to manipulate MQC to prevent mitochondrial dysfuntion during ageing hold tremendous therapeutic potential.
    Keywords:  biogenesis; metabolism; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00388.2021
  15. Nat Cancer. 2020 Oct;1(10): 941-942
    mtDNA mutations help support cancer cells.
    Hiran A Prag, Michael P Murphy.
      
    DOI:  https://doi.org/10.1038/s43018-020-00128-x
  16. Nat Commun. 2022 Feb 03. 13(1): 653
    TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.
    Jun-Ha Hwang, Kyung Min Kim, Ho Taek Oh, Gi Don Yoo, Mi Gyeong Jeong, Hyun Lee, Joori Park, Kwon Jeong, Yoon Ki Kim, Young-Gyu Ko, Eun Sook Hwang, Jeong-Ho Hong.
      Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.
    DOI:  https://doi.org/10.1038/s41467-022-28247-2
  17. Hum Mutat. 2022 Feb 02.
    Identification of a novel homozygous SCO2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.
    Andrea Gangfuß, Andreas Hentschel, Nina Rademacher, Albert Sickmann, Burkhard Stüve, Rita Horvath, Claudia Gross, Nicolai Kohlschmidt, Fabian Förster, Angela Abicht, Anne Schänzer, Ulrike Schara-Schmidt, Andreas Roos, Adela Della Marina.
      The synthesis of cytochrome c oxidase 2 (SCO2) gene encodes for a mitochondrial located metallochaperone essential for the synthesis of the cytochrome c oxidase (COX) subunit 2. Recessive mutations in SCO2 have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency and in only four cases with axonal neuropathy. Here, we identified a homozygous pathogenic variant (c.361G>C; p.(Gly121Arg)) in SCO2 in two brothers with isolated axonal motor neuropathy. To address pathogenicity of the amino acid substitution, biochemical studies were performed and revealed increased level of the mutant SCO2-protein and a dysregulation of COX subunits in leukocytes and moreover unraveled decrease of proteins involved in the manifestation of neuropathies. Hence, our combined data strengthen the concept of SCO2 being causative for a very rare form of axonal neuropathy, expand its molecular genetic spectrum and provide first biochemical insights into the underlying pathophysiology. This article is protected by copyright. All rights reserved.
    Keywords:  Charcot-Marie-Tooth disease; axonal neuropathy; synthesis of cytochrome c oxidase 2 (SCO2); white blood cell proteomics
    DOI:  https://doi.org/10.1002/humu.24338
  18. iScience. 2022 Feb 18. 25(2): 103734
    Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains.
    Arwen W Gao, Gaby El Alam, Amélia Lalou, Terytty Yang Li, Marte Molenaars, Yunyun Zhu, Katherine A Overmyer, Evgenia Shishkova, Kevin Hof, Maroun Bou Sleiman, Riekelt H Houtkooper, Joshua J Coon, Johan Auwerx.
      The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different signaling layers in animals with different genetic backgrounds is lacking. Here, we applied systems approaches to investigate the effect of UPRmt induced by doxycycline (Dox) on transcriptome, proteome, and lipidome in two genetically divergent worm strains, named N2 and CB4856. From the integrated omics datasets, we found that Dox prolongs lifespan of both worm strains through shared and strain-specific mechanisms. Specifically, Dox strongly impacts mitochondria, upregulates defense response, and lipid metabolism, while decreasing triglycerides. We further validated that lipid genes acs-2/20 and fat-7/6 were required for Dox-induced UPRmt and longevity in N2 and CB4856 worms, respectively. Our data have translational value as they indicate that the beneficial effects of Dox-induced UPRmt on lifespan are consistent across different genetic backgrounds through different regulators.
    Keywords:  Chronobiology; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.103734
  19. Circ Res. 2022 Feb 03. CIRCRESAHA121319648
    Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
    Gizem Keceli, Ashish Gupta, Joevin Sourdon, Refaat Gabr, Michael Schär, Swati Dey, Carlo G Tocchetti, Annina Stuber, Jacopo Agrimi, Yi Zhang, Michelle Leppo, Charles Steenbergen, Shenghan Lai, Lisa R Yanek, Brian O'Rourke, Gary Gerstenblith, Paul A Bottomley, Yibin Wang, Nazareno Paolocci, Robert G Weiss.
       BACKGROUND: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. To test the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.
    METHODS: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.
    RESULTS: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.
    CONCLUSIONS: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF.
    REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.
    Keywords:  antioxidants; creatine; dilatation; heart failure; myofibrils
    DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319648
  20. Front Cell Dev Biol. 2021 ;9 796128
    Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
    Alfredo Cabrera-Orefice, Alisa Potter, Felix Evers, Johannes F Hevler, Sergio Guerrero-Castillo.
      Complexome profiling (CP) is a state-of-the-art approach that combines separation of native proteins by electrophoresis, size exclusion chromatography or density gradient centrifugation with tandem mass spectrometry identification and quantification. Resulting data are computationally clustered to visualize the inventory, abundance and arrangement of multiprotein complexes in a biological sample. Since its formal introduction a decade ago, this method has been mostly applied to explore not only the composition and abundance of mitochondrial oxidative phosphorylation (OXPHOS) complexes in several species but also to identify novel protein interactors involved in their assembly, maintenance and functions. Besides, complexome profiling has been utilized to study the dynamics of OXPHOS complexes, as well as the impact of an increasing number of mutations leading to mitochondrial disorders or rearrangements of the whole mitochondrial complexome. Here, we summarize the major findings obtained by this approach; emphasize its advantages and current limitations; discuss multiple examples on how this tool could be applied to further investigate pathophysiological mechanisms and comment on the latest advances and opportunity areas to keep developing this methodology.
    Keywords:  complexome profiling; disease; mass spectrometry; mitochondria; oxidative phosphorylation; protein complex; protein-protein interaction (PPI); proteomics
    DOI:  https://doi.org/10.3389/fcell.2021.796128
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