bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–07–24
thirty-one papers selected by
Catalina Vasilescu, University of Helsinki
  1. Mitochondrial Hepatopathy.
  2. Mitochondria and mitochondrial disorders: an overview update.
  3. Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis.
  4. Expanding the phenotype of DNAJC30-associated Leigh syndrome.
  5. Crystal structure of human NADK2 reveals a dimeric organization and active site occlusion by lysine acetylation.
  6. Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
  7. Structural overview of the translocase of the mitochondrial outer membrane complex.
  8. AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.
  9. Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-eclampsia.
  10. A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers?
  11. Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila.
  12. Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.
  13. ECHS1 deficiency and its biochemical and clinical phenotype.
  14. Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency.
  15. Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.
  16. Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology.
  17. Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.
  18. Optogenetic Studies of Mitochondria.
  19. Mitochondrial ROS drive cell cycle progression.
  20. From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy.
  21. Transfer of H2O2 from Mitochondria to the endoplasmic reticulum via Aquaporin-11.
  22. The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity.
  23. The emerging landscape of spatial profiling technologies.
  24. Balancing energy and protein homeostasis at ER-mitochondria contact sites.
  25. TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
  26. Connexin 43 in Mitochondria: What Do We Really Know About Its Function?
  27. Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise studies.
  28. Estimating the number of diseases - the concept of rare, ultra-rare, and hyper-rare.
  29. Recommendations for clinical interpretation of variants found in non-coding regions of the genome.
  30. The sequences of 150,119 genomes in the UK Biobank.
  31. Mitochondrial-derived peptides as a novel intervention for obesity and cardiac diseases: bench evidence for potential bedside application.
  1. Clin Liver Dis. 2022 Aug;pii: S1089-3261(22)00020-4. [Epub ahead of print]26(3): 421-438
    Mitochondrial Hepatopathy.
    Mary Ayers, Simon P Horslen, Anna María Gómez, James E Squires.
      Mitochondrial hepatopathies are a subset of mitochondrial diseases defined by primary dysfunction of hepatocyte mitochondria leading to a phenotype of hepatocyte cell injury, steatosis, or liver failure. Increasingly, the diagnosis is established by new sequencing approaches that combine analysis of both nuclear DNA and mitochondrial DNA and allow for timely diagnosis in most patients. Despite advances in diagnostics, for most affected children their disorders are relentlessly progressive, and result in substantial morbidity and mortality. Treatment remains mainly supportive; however, novel therapeutics and a more definitive role for liver transplantation hold promise for affected children.
    Keywords:  Acute liver failure; Children; Hepatocerebral dysfunction; Mitochondrial disease
    DOI:  https://doi.org/10.1016/j.cld.2022.03.006
  2. Endocr Regul. 2022 Jul 13. 56(3): 232-248
    Mitochondria and mitochondrial disorders: an overview update.
    Vibhuti Rambani, Dominika Hromnikova, Daniela Gasperikova, Martina Skopkova.
      Mitochondria, the cell powerhouse, are membrane-bound organelles present in the cytoplasm of almost all the eukaryotic cells. Their main function is to generate energy in the form of adenosine triphosphate (ATP). In addition, mitochondria store calcium for the cell signaling activities, generate heat, harbor pathways of intermediate metabolism and mediate cell growth and death. Primary mitochondrial diseases (MDs) form a clinically as well as genetically heterogeneous group of inherited disorders that result from the mitochondrial energetic metabolism malfunctions. The lifetime risk of the MDs development is estimated at 1:1470 of newborns, which makes them one of the most recurrent groups of inherited disorders with an important burden for society. MDs are progressive with wide range of symptoms of variable severity that can emerge congenitally or anytime during the life. MD can be caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA genes. Mutations inducing impairment of mitochondrial function have been found in more than 400 genes. Furthermore, more than 1200 nuclear genes, which could play a role in the MDs' genetic etiology, are involved in the mitochondrial activities. However, the knowledge regarding the mechanism of the mitochondrial pathogenicity appears to be most essential for the development of effective patient's treatment suffering from the mitochondrial disease. This is an overview update focused on the mitochondrial biology and the mitochondrial diseases associated genes.
    Keywords:  genes; inherited disorder; mitochondria
    DOI:  https://doi.org/10.2478/enr-2022-0025
  3. AIDS. 2022 Jul 15.
    Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis.
    Matthew Hunt, Megan M Mcniff, Amy E Vincent, Caroline Sabin, Alan Winston, Brendan A I Payne.
       OBJECTIVE: To quantify mitochondrial function in skeletal muscle of people treated with contemporary antiretroviral therapy.
    DESIGN: Cross-sectional observational study.
    METHODS: Quantitative multiplex immunofluorescence was performed to determine mitochondrial mass and respiratory chain complex abundance in individual myofibres from tibialis anterior biopsies. Individual myofibres were captured by laser microdissection and mitochondrial DNA (mtDNA) content and large-scale deletions were measured by real-time PCR.
    RESULTS: Forty five antiretroviral therapy (ART) treated people with HIV (PWH, mean age 58 years, mean duration of ART 125 months) were compared with 15 HIV negative age-matched controls. Mitochondrial complex I (CI) deficiency was observed at higher proportional levels in PWH than negative controls (P = 0.008). Myofibre mitochondrial mass did not differ by HIV status.No ART class was significantly associated with mitochondrial deficiency, including prior exposure to historical NRTIs (nucleoside analogue reverse transcriptase inhibitors) associated with systemic mitochondrial toxicity.To exclude an effect of untreated HIV, we also studied skeletal muscle from 13 ART-naïve PWH (mean age 37). These showed negligible CI defects, as well as comparable myofibre mitochondrial mass to ART-treated PWH.Most CI-deficient myofibres contained mtDNA deletions. No mtDNA depletion was detected.
    CONCLUSION: Here, we show that PWH treated with contemporary ART have mitochondrial dysfunction in skeletal muscle, exceeding that expected due to age alone. Surprisingly, this was not mediated by prior exposure to mitochondrially toxic NRTIs, suggesting novel mechanisms of mitochondrial dysfunction in contemporary ART-treated PWH. These findings are relevant for better understanding successful ageing in PWH.
    DOI:  https://doi.org/10.1097/QAD.0000000000003334
  4. Clin Genet. 2022 Jul 21.
    Expanding the phenotype of DNAJC30-associated Leigh syndrome.
    Marta Zawadzka, Magdalena Krygier, Małgorzata Pawłowicz, Matheus Vernet Machado Bressan Wilke, Karolina Rutkowska, Naig Gueguen, Valerie Desquiret-Dumas, Eric W Klee, Lisa A Schimmenti, Jarosław Sławek, Vincent Procaccio, Rafał Płoski, Maria Mazurkiewicz-Bełdzińska.
      Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement. This article is protected by copyright. All rights reserved.
    Keywords:  DNAJC30; Leigh syndrome; basal ganglia; dystonia; dystonic gait; mitochondrial disease; neurodegenerative disease; optic neuropathy; spasticity
    DOI:  https://doi.org/10.1111/cge.14196
  5. Mol Cell. 2022 Jul 13. pii: S1097-2765(22)00609-8. [Epub ahead of print]
    Crystal structure of human NADK2 reveals a dimeric organization and active site occlusion by lysine acetylation.
    Charline Mary, Mona Hoseini Soflaee, Rushendhiran Kesavan, Muriel Gelin, Harrison Brown, G Zacharias, Thomas P Mathews, Andrew Lemoff, Corinne Lionne, Gilles Labesse, Gerta Hoxhaj.
      NAD+ kinases (NADKs) are metabolite kinases that phosphorylate NAD+ molecules to make NADP+, a limiting substrate for the generation of reducing power NADPH. NADK2 sustains mitochondrial NADPH production that enables proline biosynthesis and antioxidant defense. However, its molecular architecture and mechanistic regulation remain undescribed. Here, we report the crystal structure of human NADK2, revealing a substrate-driven mode of activation. We find that NADK2 presents an unexpected dimeric organization instead of the typical tetrameric assemblage observed for other NADKs. A specific extended segment (aa 325-365) is crucial for NADK2 dimerization and activity. Moreover, we characterize numerous acetylation events, including those on Lys76 and Lys304, which reside near the active site and inhibit NADK2 activity without disrupting dimerization, thereby reducing mitochondrial NADP(H) production, proline synthesis, and cell growth. These findings reveal important molecular insight into the structure and regulation of a vital enzyme in mitochondrial NADPH and proline metabolism.
    Keywords:  NAD kinases; NADK2; NADPH metabolism; crystal structure; mitochondrial metabolism; post-translational modifications; proline metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.026
  6. Cell Rep. 2022 Jul 19. pii: S2211-1247(22)00930-5. [Epub ahead of print]40(3): 111124
    Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
    Alberto Danese, Simone Patergnani, Alessandra Maresca, Camille Peron, Andrea Raimondi, Leonardo Caporali, Saverio Marchi, Chiara La Morgia, Valentina Del Dotto, Claudia Zanna, Angelo Iannielli, Alice Segnali, Ivano Di Meo, Andrea Cavaliere, Magdalena Lebiedzinska-Arciszewska, Mariusz R Wieckowski, Andrea Martinuzzi, Milton N Moraes-Filho, Solange R Salomao, Adriana Berezovsky, Rubens Belfort, Christopher Buser, Fred N Ross-Cisneros, Alfredo A Sadun, Carlo Tacchetti, Vania Broccoli, Carlotta Giorgi, Valeria Tiranti, Valerio Carelli, Paolo Pinton.
      Leber's hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.
    Keywords:  CP: Neuroscience; LHON; autophagy; cybrids; iPSCs; mitochondria; mitophagy; mtDNA; optic nerve; retinal ganglion cells; therapy
    DOI:  https://doi.org/10.1016/j.celrep.2022.111124
  7. Biophys Physicobiol. 2022 ;19 e190022
    Structural overview of the translocase of the mitochondrial outer membrane complex.
    Yuhei Araiso, Toshiya Endo.
      Most mitochondrial proteins are synthesized as precursor proteins (preproteins) in the cytosol and imported into mitochondria. The translocator of the outer membrane (TOM) complex functions as a main entry gate for the import of mitochondrial proteins. The TOM complex is a multi-subunit membrane protein complex composed of a β-barrel channel Tom40 and six single-pass membrane proteins. Recent cryo-EM studies have revealed high-resolution structures of the yeast and human TOM complexes, which enabled us to discuss the mechanism of protein import at an amino-acid residue level. The cryo-EM structures show that two Tom40 β-barrels are surrounded by two sets of small Tom subunits to form a dimeric structure. The intermembrane space (IMS) domains of Tom40, Tom22, and Tom7 form a binding site for presequence-containing preproteins in the middle of the dimer to achieve their efficient transfer of to the downstream translocase, the TIM23 complex. The N-terminal segment of Tom40 spans the channel from the cytosol to the IMS to interact with Tom5 at the periphery of the dimer, where downstream components of presequence-lacking preproteins are recruited. Structure-based biochemical analyses together with crosslinking experiments revealed that each Tom40 channel possesses two distinct paths and exit sites for protein translocation of different sets of mitochondrial preproteins. Here we summarize the current knowledge on the structural features, protein translocation mechanisms, and remaining questions for the TOM complexes, with particular emphasis on their determined cryo-EM structures. This article is an extended version of the Japanese article, Structural basis for protein translocation by the translocase of the outer mitochondrial membrane, published in SEIBUTSU BUTSURI Vol. 60, p. 280-283 (2020).
    Keywords:  Cryo-EM; TOM complex preprotein; mitochondria; protein translocation
    DOI:  https://doi.org/10.2142/biophysico.bppb-v19.0022
  8. EMBO J. 2022 Jul 20. e110784
    AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.
    Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klußmann, Ines Neundorf, David A Stroud, Michael T Ryan, Aleksandra Trifunovic, Ulrich Brandt, Jan Riemer.
      The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.
    Keywords:  AIFM1; MIA40-CHCHD4; NDUFS5; complex I; mitochondrial disulfide relay
    DOI:  https://doi.org/10.15252/embj.2022110784
  9. Hum Hered. 2022 Jul 18.
    Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-eclampsia.
    Baohua Zhou, Xuelian Chu, Caijuan Zhang, Xiufeng Liang.
       OBJECTIVES: Impairment of mitochondrial function caused by pathogenic mitochondrial DNA (mtDNA) mutations has been found to be associated with pre-eclampsia (PE). However, the underlying mechanism of PE remains poorly undetermined. The aim of this study is to evaluate the relationship between mitochondrial tRNAs (mt-tRNAs) variants and PE.
    MATERIAL AND METHODS: The mt-tRNAs variants in a cohort of 100 pregnant women with PE and 100 healthy subjects were examined by PCR-Sager sequencing. Moreover, the phylogenetic conservation analysis, mitochondrial haplogroup analysis, as well as pathogenicity scoring system were used to assess the potential pathogenicity of these tRNA variants.
    RESULTS: We identified five possible pathogenic mt-tRNA variants: tRNAPhe A608G, tRNAIle A4263G, tRNAAla T5587C, tRNALeu(CUN) G12294C and tRNAPro G15995A. We noticed that these variants were not detected in control subjects and occurred at the positions which were extremely conserved. Alternations in tRNAs structure caused by these variants may lead to the failures in tRNAs metabolism, which may subsequently may lead to the impairment of mitochondrial translation, as well as the respiratory chain functions. Thus, mt-tRNA variants may be involved in the pathogenesis of PE.
    CONCLUSIONS: Taken together, our data indicated that variants in mt-tRNA genes were the important contributors to PE; screening for mt-tRNA variants was recommended for early detection and prevention of PE.
    DOI:  https://doi.org/10.1159/000525663
  10. J Gen Physiol. 2022 Sep 05. pii: e202213167. [Epub ahead of print]154(9):
    A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers?
    Carlo Reggiani, Lorenzo Marcucci.
      Mitochondria are characterized by a high capacity to accumulate calcium thanks to the electrochemical gradient created by the extrusion of protons in the respiratory chain. Thereby calcium can enter crossing the inner mitochondrial membrane via MCU complex, a high-capacity, low-affinity transport mechanism. Calcium uptake serves numerous purposes, among them the regulation of three dehydrogenases of the citric cycle, apoptosis via permeability transition, and, in some cell types, modulation of cytosolic calcium transients. This Review is focused on mitochondrial calcium uptake in skeletal muscle fibers and aims to reanalyze its functional impact. In particular, we ask whether mitochondrial calcium uptake is relevant for the control of cytosolic calcium transients and therefore of contractile performance. Recent data suggest that this may be the case, at least in particular conditions, as modified expression of MCU complex subunits or of proteins involved in mitochondrial dynamics and ablation of the main cytosolic calcium buffer, parvalbumin.
    DOI:  https://doi.org/10.1085/jgp.202213167
  11. Nature. 2022 Jul 20.
    Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila.
    Xin Gu, Patrick Jouandin, Pranav V Lalgudi, Rich Binari, Max L Valenstein, Michael A Reid, Annamarie E Allen, Nolan Kamitaki, Jason W Locasale, Norbert Perrimon, David M Sabatini.
      Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine1. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation2,3, but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin-null flies (Sesn-/-) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet. Knock-in flies expressing a leucine-binding-deficient Sestrin mutant (SesnL431E) have reduced, leucine-insensitive mTORC1 activity. Notably, we find that flies can discriminate between food with or without leucine, and preferentially feed and lay progeny on leucine-containing food. This preference depends on Sestrin and its capacity to bind leucine. Leucine regulates mTORC1 activity in glial cells, and knockdown of Sesn in these cells reduces the ability of flies to detect leucine-free food. Thus, nutrient sensing by mTORC1 is necessary for flies not only to adapt to, but also to detect, a diet deficient in an essential nutrient.
    DOI:  https://doi.org/10.1038/s41586-022-04960-2
  12. Biogerontology. 2022 Jul 16.
    Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.
    Elangbam Tomtheelnganbee, Puja Sah, R Sharma.
      Ageing is accompanied by alterations in several biochemical processes, highly influenced by its environment. It is controlled by the interactions at various levels of biological hierarchy. To maintain homeostasis, a number of nutrient sensors respond to the nutritional status of the cell and control its energy metabolism. Mitochondrial physiology is influenced by the energy status of the cell. The alterations in mitochondrial physiology and the network of nutrient sensors result in mitochondrial damage leading to age related metabolic degeneration and diseases. Calorie restriction (CR) has proved to be as the most successful intervention to achieve the goal of longevity and healthspan. CR elicits a hormetic response and regulates metabolism by modulating these networks. In this review, the authors summarize the interdependent relationship between mitochondrial physiology and nutrient sensors during the ageing process and their role in regulating metabolism.
    Keywords:  AMPK; Ageing; Dietary restriction; Mitochondria; Sirtuins; mTOR
    DOI:  https://doi.org/10.1007/s10522-022-09978-7
  13. Am J Med Genet A. 2022 Jul 20.
    ECHS1 deficiency and its biochemical and clinical phenotype.
    Can Ozlu, Priya Chelliah, Hamza Dahshi, Daniel Horton, Veronica B Edgar, Souad Messahel, Saima Kayani.
      ECHS1 gene encodes a mitochondrial enzyme, short-chain enoyl-CoA hydratase (SCEH). SCEH is involved in fatty acid oxidation ([Sharpe and McKenzie (2018); Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency, 7: 46]) and valine catabolism ([Fong and Schulz (1977); Purification and properties of pig heart crotonase and the presence of short chain and long chain enoyl coenzyme A hydratases in pig and guinea pig tissues, 252: 542-547]; [Wanders et al. (2012); Enzymology of the branched-chain amino acid oxidation disorders: The valine pathway, 35: 5-12]), and the dysfunction of SCEH leads to a severe Leigh or Leigh-like Syndrome phenotype in patients ([Haack et al. (2015); Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement, 2: 492-509]; [Peters et al. (2014); ECHS1 mutations in Leigh disease: A new inborn error of metabolism affecting valine metabolism, 137: 2903-2908]; [Sakai et al. (2015); ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome, 36: 232-239]; [Tetreault et al. (2015); Whole-exome sequencing identifies novel ECHS1 mutations in Leigh, 134: 981-991]). This study aims to further describe the ECHS1 deficiency phenotype using medical history questionnaires and standardized tools assessing quality of life and adaptive skills. Our findings in this largest sample of ECHS1 patients in literature to date (n = 13) illustrate a severely disabling condition causing severe developmental delays (n = 11), regression (n = 10), dystonia/hypotonia and movement disorders (n = 13), commonly with symptom onset in infancy (n = 10), classical MRI findings involving the basal ganglia (n = 11), and variability in biochemical profile. Congruent with the medical history, our patients had significantly low composite and domain scores on Vineland Adaptive Behavior Scales, Third Edition. We believe there is an increasing need for better understanding of ECHS1 deficiency with an aim to support the development of transformative genetic-based therapies, driven by the unmet need for therapies for patients with this genetic disease.
    Keywords:  ECHS1; Leigh syndrome; Leigh-like syndrome; metabolic encephalopathy
    DOI:  https://doi.org/10.1002/ajmg.a.62895
  14. J Inherit Metab Dis. 2022 Jul 22.
    Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency.
    Nicole J Van Bergen, Adhish S Walvekar, Myrto Patraskaki, Tim Sikora, Carole L Linster, John Christodoulou.
      The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX. Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients. As more patients are identified, distinct clinical features are emerging depending on the location of the pathogenic variant. In this review, we carefully catalogued the clinical features of all published NAXD deficiency patients and found distinct patterns in clinical presentations depending on which subcellular compartment is affected by the enzymatic deficiency. Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions. Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration. This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage. A deeper understanding of the clinical phenotype may facilitate rapid identification of new cases and allow earlier therapeutic intervention. Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments. This article is protected by copyright. All rights reserved.
    Keywords:  NAXD deficiency; NAXE deficiency; febrile illness; metabolism; metabolite repair; neurodegeneration; skin lesions
    DOI:  https://doi.org/10.1002/jimd.12541
  15. Nature. 2022 Jul 20.
    Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.
    Aida Rodríguez-Nuevo, Ariadna Torres-Sanchez, Juan M Duran, Cristian De Guirior, Maria Angeles Martínez-Zamora, Elvan Böke.
      Oocytes form before birth and remain viable for several decades before fertilization1. Although poor oocyte quality accounts for most female fertility problems, little is known about how oocytes maintain cellular fitness, or why their quality eventually declines with age2. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilization and embryo survival3-5. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced electron transport chain. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report a physiological cell type without complex I in animals. Our findings also clarify why patients with complex-I-related hereditary mitochondrial diseases do not experience subfertility. Complex I suppression represents an evolutionarily conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.
    DOI:  https://doi.org/10.1038/s41586-022-04979-5
  16. Cell Mol Life Sci. 2022 Jul 17. 79(8): 428
    Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology.
    Vincenzo Zara, Graziana Assalve, Alessandra Ferramosca.
      The citrate carrier (CIC) is an integral protein of the inner mitochondrial membrane which catalyzes the efflux of mitochondrial citrate (or other tricarboxylates) in exchange with a cytosolic anion represented by a tricarboxylate or a dicarboxylate or phosphoenolpyruvate. In this way, the CIC provides the cytosol with citrate which is involved in many metabolic reactions. Several studies have been carried out over the years on the structure, function and regulation of this metabolite carrier protein both in mammals and in many other organisms. A lot of data on the characteristics of this protein have therefore accumulated over time thereby leading to a complex framework of metabolic and physiological implications connected to the CIC function. In this review, we critically analyze these data starting from the multiple roles played by the mitochondrial CIC in many cellular processes and then examining the regulation of its activity in different nutritional and hormonal states. Finally, the metabolic significance of the citrate flux, mediated by the CIC, across distinct subcellular compartments is also discussed.
    Keywords:  Citrate; Intermediary metabolism; Metabolic network; Metabolite carrier; Mitochondria; Subcellular compartments
    DOI:  https://doi.org/10.1007/s00018-022-04466-0
  17. Commun Biol. 2022 Jul 18. 5(1): 717
    Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy.
    Yingli Gu, Flora Guerra, Mingzheng Hu, Alexander Pope, Kijung Sung, Wanlin Yang, Simone Jetha, Thomas A Shoff, Tessanya Gunatilake, Owen Dahlkamp, Linda Zhixia Shi, Fiore Manganelli, Maria Nolano, Yue Zhou, Jianqing Ding, Cecilia Bucci, Chengbiao Wu.
      Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7V162M mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic fibroblasts (MEFs). Primary cultured E18 dorsal root ganglion (DRG) sensory neurons also show mitochondrial fragmentation and altered axonal mitochondrial movement. In addition, we demonstrate that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalize the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study reveals, for the first time, that expression of CMT2B Rab7 mutation at the physiological level enhances Drp1 activity to promote mitochondrial fission, potentially underlying selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.
    DOI:  https://doi.org/10.1038/s42003-022-03632-1
  18. Methods Mol Biol. 2022 ;2501 311-324
    Optogenetic Studies of Mitochondria.
    Kai Chen, Patrick Ernst, Xiaoguang Margaret Liu, Lufang Zhou.
      While optogenetic approaches have been widely used for remote control of cell membrane excitability and intracellular signaling pathways, their application in mitochondrial study has been limited, largely due to the challenge of effectively and specifically expressing heterologous light-gated rhodopsin channels in the mitochondria. Here, we describe the methods for expressing functional channelrhodopsin 2 (ChR2) proteins in the mitochondrial inner membrane with an unusually long mitochondrial leading sequence and characterizing optogenetic-mediated mitochondrial membrane potential (ΔΨm) depolarization. We then illustrate how this next-generation optogenetic approach can be used to study the effect of ΔΨm on mitochondrial functions such as mitophagy, programed cell death, and preconditioning-mediated cytoprotection. We anticipate that this innovative technology will enable new insights into the mechanisms by which changes in ΔΨm differentially impacts mitochondrial and cellular functions.
    Keywords:  Apoptosis; Mitochondria; Mitochondrial protein import; Mitophagy; Optogenetics; Preconditioning
    DOI:  https://doi.org/10.1007/978-1-0716-2329-9_15
  19. Nat Rev Mol Cell Biol. 2022 Jul 20.
    Mitochondrial ROS drive cell cycle progression.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-022-00523-5
  20. Cold Spring Harb Perspect Med. 2022 Jul 21. pii: a041282. [Epub ahead of print]12(6):
    From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy.
    Benson S Chen, Patrick Yu-Wai-Man.
      Leber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial disorder that presents with severe bilateral sequential vision loss, due to the selective degeneration of retinal ganglion cells (RGCs). Since the mitochondrial genetic basis for LHON was uncovered in 1988, considerable progress has been made in understanding the pathogenetic mechanisms driving RGC loss, which has enabled the development of therapeutic approaches aimed at mitigating the underlying mitochondrial dysfunction. In this review, we explore the genetics of LHON, from bench to bedside, focusing on the pathogenetic mechanisms and how these have informed the development of different gene therapy approaches, in particular the technique of allotopic expression with adeno-associated viral vectors. Finally, we provide an overview of the recent gene therapy clinical trials and consider the unanswered questions, challenges, and future prospects.
    DOI:  https://doi.org/10.1101/cshperspect.a041282
  21. Redox Biol. 2022 Jul 16. pii: S2213-2317(22)00182-3. [Epub ahead of print]55 102410
    Transfer of H2O2 from Mitochondria to the endoplasmic reticulum via Aquaporin-11.
    Ilaria Sorrentino, Mauro Galli, Iria Medraño-Fernandez, Roberto Sitia.
      Some aquaporins (AQPs) can transport H2O2 across membranes, allowing redox signals to proceed in and between cells. Unlike other peroxiporins, human AQP11 is an endoplasmic reticulum (ER)-resident that can conduit H2O2 to the cytosol. Here, we show that silencing Ero1α, an ER flavoenzyme that generates abundant H2O2 during oxidative folding, causes a paradoxical increase in luminal H2O2 levels. The simultaneous AQP11 downregulation prevents this increase, implying that H2O2 reaches the ER from an external source(s). Pharmacological inhibition of the electron transport chain reveals that Ero1α downregulation activates superoxide production by complex III. In the intermembrane space, superoxide dismutase 1 generates H2O2 that enters the ER channeled by AQP11. Meanwhile, the number of ER-mitochondria contact sites increases as well, irrespective of AQP11 expression. Taken together, our findings identify a novel interorganellar redox response that is activated upon Ero1α downregulation and transfers H2O2 from mitochondria to the ER via AQP11.
    Keywords:  Complex III; Hydrogen peroxide; Interorganellar crosstalk/ peroxiporin; Mitochondrial-associated membranes; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.redox.2022.102410
  22. Sci Adv. 2022 Jul 22. 8(29): eabo0155
    The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity.
    Marie Paradis, Nicole Kucharowski, Gabriela Edwards Faret, Santiago José Maya Palacios, Christian Meyer, Birgit Stümpges, Isabell Jamitzky, Julia Kalinowski, Christoph Thiele, Reinhard Bauer, Achim Paululat, Julia Sellin, Margret Helene Bülow.
      Dynamic contacts are formed between endoplasmic reticulum (ER) and mitochondria that enable the exchange of calcium and phospholipids. Disturbed contacts between ER and mitochondria impair mitochondrial dynamics and are a molecular hallmark of Parkinson's disease, which is also characterized by impaired complex I activity and dopaminergic neuron degeneration. Here, we analyzed the role of cysteine-rich with EGF-like domain (Creld), a poorly characterized risk gene for Parkinson's disease, in the regulation of mitochondrial dynamics and function. We found that loss of Creld leads to mitochondrial hyperfusion and reduced ROS signaling in Drosophila melanogaster, Xenopus tropicalis, and human cells. Creld fly mutants show differences in ER-mitochondria contacts and reduced respiratory complex I activity. The resulting low-hydrogen peroxide levels are linked to disturbed neuronal activity and lead to impaired locomotion, but not neurodegeneration, in Creld mutants. We conclude that Creld regulates ER-mitochondria communication and thereby hydrogen peroxide formation, which is required for normal neuron function.
    DOI:  https://doi.org/10.1126/sciadv.abo0155
  23. Nat Rev Genet. 2022 Jul 20.
    The emerging landscape of spatial profiling technologies.
    Jeffrey R Moffitt, Emma Lundberg, Holger Heyn.
      Improved scale, multiplexing and resolution are establishing spatial nucleic acid and protein profiling methods as a major pillar for cellular atlas building of complex samples, from tissues to full organisms. Emerging methods yield omics measurements at resolutions covering the nano- to microscale, enabling the charting of cellular heterogeneity, complex tissue architectures and dynamic changes during development and disease. We present an overview of the developing landscape of in situ spatial genome, transcriptome and proteome technologies, exemplify their impact on cell biology and translational research, and discuss current challenges for their community-wide adoption. Among many transformative applications, we envision that spatial methods will map entire organs and enable next-generation pathology.
    DOI:  https://doi.org/10.1038/s41576-022-00515-3
  24. Sci Signal. 2022 Jul 05. 15(741): eabm7524
    Balancing energy and protein homeostasis at ER-mitochondria contact sites.
    Amado Carreras-Sureda, Guido Kroemer, Julio Cesar Cardenas, Claudio Hetz.
      The endoplasmic reticulum (ER) is the largest organelle of the cell and participates in multiple essential functions, including the production of secretory proteins, lipid synthesis, and calcium storage. Sustaining proteostasis requires an intimate coupling with energy production. Mitochondrial respiration evolved to be functionally connected to ER physiology through a physical interface between both organelles known as mitochondria-associated membranes. This quasi-synaptic structure acts as a signaling hub that tunes the function of both organelles in a bidirectional manner and controls proteostasis, cell death pathways, and mitochondrial bioenergetics. Here, we discuss the main signaling mechanisms governing interorganellar communication and their putative role in diseases including cancer and neurodegeneration.
    DOI:  https://doi.org/10.1126/scisignal.abm7524
  25. Nat Metab. 2022 Jul 21.
    TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
    Ev-Marie Schuster, Maximilian W Epple, Katharina M Glaser, Michael Mihlan, Kerstin Lucht, Julia A Zimmermann, Anna Bremser, Aikaterini Polyzou, Nadine Obier, Nina Cabezas-Wallscheid, Eirini Trompouki, Andrea Ballabio, Jörg Vogel, Joerg M Buescher, Alexander J Westermann, Angelika S Rambold.
      Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB-Irg1-itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32-BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB's role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s42255-022-00605-w
  26. Front Physiol. 2022 ;13 928934
    Connexin 43 in Mitochondria: What Do We Really Know About Its Function?
    Kerstin Boengler, Luc Leybaert, Marisol Ruiz-Meana, Rainer Schulz.
      Connexins are known for their ability to mediate cell-cell communication via gap junctions and also form hemichannels that pass ions and molecules over the plasma membrane when open. Connexins have also been detected within mitochondria, with mitochondrial connexin 43 (Cx43) being the best studied to date. In this review, we discuss evidence for Cx43 presence in mitochondria of cell lines, primary cells and organs and summarize data on its localization, import and phosphorylation status. We further highlight the influence of Cx43 on mitochondrial function in terms of respiration, opening of the mitochondrial permeability transition pore and formation of reactive oxygen species, and also address the presence of a truncated form of Cx43 termed Gja1-20k. Finally, the role of mitochondrial Cx43 in pathological conditions, particularly in the heart, is discussed.
    Keywords:  GJA1-20k; connexin; hemichannel; ischemia-reperfusion injury; mitochondria; preconditioning
    DOI:  https://doi.org/10.3389/fphys.2022.928934
  27. PLoS One. 2022 ;17(7): e0270951
    Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise studies.
    Stephanie Y Yang, Caleb S Mirabal, Charles E Newcomb, Kerry J Stewart, Dan E Arking.
      Mitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).
    DOI:  https://doi.org/10.1371/journal.pone.0270951
  28. iScience. 2022 Aug 19. 25(8): 104698
    Estimating the number of diseases - the concept of rare, ultra-rare, and hyper-rare.
    C I Edvard Smith, Peter Bergman, Daniel W Hagey.
      At the dawn of the personalized medicine era, the number of rare diseases has been estimated at 10,000. By considering the influence of environmental factors together with genetic variations and our improved diagnostic capabilities, an assessment suggests a considerably larger number. The majority would be extremely rare, and hence, we introduce the term "hyper-rare," defined as affecting <1/108 individuals. Such disorders would potentially outnumber all currently known rare diseases. Because autosomal recessive disorders are likely concentrated in consanguineous populations, and rare toxicities in rural areas, establishing their existence necessitates a greater reach than is currently viable. Moreover, the randomness of X-linked and gain-of-function mutations greatly compound this challenge. However, whether concurrent diseases actually cause a distinct illness will depend on if their pathological mechanisms interact (phenotype conversion) or not (phenotype maintenance). The hyper-rare disease concept will be important in precision medicine with improved diagnosis and treatment of rare disease patients.
    Keywords:  Biological sciences; Clinical genetics; Genetics Disease; Health sciences; Human genetics
    DOI:  https://doi.org/10.1016/j.isci.2022.104698
  29. Genome Med. 2022 Jul 19. 14(1): 73
    Recommendations for clinical interpretation of variants found in non-coding regions of the genome.
    Jamie M Ellingford, Joo Wook Ahn, Richard D Bagnall, Diana Baralle, Stephanie Barton, Chris Campbell, Kate Downes, Sian Ellard, Celia Duff-Farrier, David R FitzPatrick, John M Greally, Jodie Ingles, Neesha Krishnan, Jenny Lord, Hilary C Martin, William G Newman, Anne O'Donnell-Luria, Simon C Ramsden, Heidi L Rehm, Ebony Richardson, Moriel Singer-Berk, Jenny C Taylor, Maggie Williams, Jordan C Wood, Caroline F Wright, Steven M Harrison, Nicola Whiffin.
       BACKGROUND: The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.
    METHODS: We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.
    RESULTS: We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants.
    CONCLUSIONS: These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
    Keywords:  Gene regulation; Non-coding variation; Variant interpretation
    DOI:  https://doi.org/10.1186/s13073-022-01073-3
  30. Nature. 2022 Jul 20.
    The sequences of 150,119 genomes in the UK Biobank.
    DBDS Genetic Consortium
      Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank3. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.
    DOI:  https://doi.org/10.1038/s41586-022-04965-x
  31. J Clin Pathol. 2022 Jul 21. pii: jclinpath-2022-208321. [Epub ahead of print]
    Mitochondrial-derived peptides as a novel intervention for obesity and cardiac diseases: bench evidence for potential bedside application.
    Wichida Kaorop, Chayodom Maneechote, Sirinart Kumfu, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Currently, obesity is the most common major health problem for people worldwide. Obesity is known to be a significant risk factor for several diseases, including metabolic syndrome, insulin resistance and type 2 diabetes, eventually leading to the development of chronic systemic disorders. Previous studies showed that mitochondrial dysfunction could be one of the potential mechanisms for obesity progression. Most interventions used for combating obesity have also been reported to modulate mitochondrial function, suggesting the potential role of mitochondria in the pathology of the obese condition. Recent studies have shown that peptides produced by mitochondria, mitochondrial-derived peptides (MDPs), potentially improve metabolic function and exert benefits in obesity-associated diabetes and various heart pathologies. In this review, the roles of MDPs in the metabolic pathways and their use in the treatment of various adverse effects of obesity are comprehensively summarised based on collective evidence from in vitro, in vivo and clinical studies. The roles of MDPs as novel therapeutic interventions for cardiac dysfunction caused by various stresses or toxicities are also presented and discussed. This review aims to summarise the knowledge regarding the effects of MDPs on obesity, with a particular emphasis on their potential protective effects on the impaired cardiac function associated with obesity. The information from this review will also encourage further clinical investigations to warrant the potential application of MDP interventions in the clinical setting in the future.
    Keywords:  apoptosis; diabetes mellitus; heart; myocardial ischemia; pathology, molecular
    DOI:  https://doi.org/10.1136/jcp-2022-208321
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