bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2022‒03‒06
thirteen papers selected by
Flavia Söllner
Ludwig-Maximilians University
  1. Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease.
  2. Autophagy deficiency abolishes liver mitochondrial DNA segregation.
  3. Heteroplasmy of Wild Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
  4. Long-lived mitochondrial proteins and why they exist.
  5. Exploring statistical weight estimates for mitochondrial DNA matches involving heteroplasmy.
  6. Mitochondrial ribosomal protein genes connected with Alzheimer's and tellurite toxicity.
  7. Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology.
  8. Mitochondrial Sirtuins in Parkinson's Disease.
  9. SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA.
  10. Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection.
  11. Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes.
  12. NAD+ in COVID-19 and viral infections.
  13. LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.
  1. Front Cardiovasc Med. 2021 ;8 808115
    Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease.
    Haiying Wang, Yijun Han, Shenwei Li, Yunan Chen, Yafen Chen, Jing Wang, Yuqing Zhang, Yawen Zhang, Jingsuo Wang, Yong Xia, Jinxiang Yuan.
      Mitochondria is a ubiquitous, energy-supplying (ATP-based) organelle found in nearly all eukaryotes. It acts as a "power plant" by producing ATP through oxidative phosphorylation, providing energy for the cell. The bioenergetic functions of mitochondria are regulated by nuclear genes (nDNA). Mitochondrial DNA (mtDNA) and respiratory enzymes lose normal structure and function when nuclear genes encoding the related mitochondrial factors are impaired, resulting in deficiency in energy production. Massive generation of reactive oxygen species and calcium overload are common causes of mitochondrial diseases. The mitochondrial depletion syndrome (MDS) is associated with the mutations of mitochondrial genes in the nucleus. It is a heterogeneous group of progressive disorders characterized by the low mtDNA copy number. TK2, FBXL4, TYPM, and AGK are genes known to be related to MDS. More recent studies identified new mutation loci associated with this disease. Herein, we first summarize the structure and function of mitochondria, and then discuss the characteristics of various types of MDS and its association with cardiac diseases.
    Keywords:  ATP; cardiac disease; mitochondrial DNA depletion syndrome; mtDNA; nuclear gene mutation
    DOI:  https://doi.org/10.3389/fcvm.2021.808115
  2. Autophagy. 2022 Feb 27. 1-12
    Autophagy deficiency abolishes liver mitochondrial DNA segregation.
    Katiane Tostes, Angélica C Dos Santos, Lindomar O Alves, Luiz R G Bechara, Rachel Marascalchi, Carolina H Macabelli, Mateus P Grejo, William T Festuccia, Roberta A Gottlieb, Julio C B Ferreira, Marcos R Chiaratti.
      Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, co-existence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, the mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and cell-specific fashion, potentially leading to disease. Segregation of mtDNA is mainly evident in hepatic cells, resulting in an age-dependent increase of mtDNA variants, including non-synonymous potentially deleterious mutations. Here we modeled mtDNA segregation using a well-established heteroplasmic mouse line with mtDNA of NZB/BINJ and C57BL/6N origin on a C57BL/6N nuclear background. This mouse line showed a pronounced age-dependent NZB mtDNA accumulation in the liver, thus leading to enhanced respiration capacity per mtDNA molecule. Remarkably, liver-specific atg7 (autophagy related 7) knockout abolished NZB mtDNA accumulat ion, resulting in close-to-neutral mtDNA segregation through development into adulthood. prkn (parkin RBR E3 ubiquitin protein ligase) knockout also partially prevented NZB mtDNA accumulation in the liver, but to a lesser extent. Hence, we propose that age-related liver mtDNA segregation is a consequence of macroautophagic clearance of the less-fit mtDNA. Considering that NZB/BINJ and C57BL/6N mtDNAs have a level of divergence comparable to that between human Eurasian and African mtDNAs, these findings have potential implications for humans, including the safe use of mitochondrial replacement therapy.
    Keywords:  Atg7; NZB; heteroplasmy; mitochondria; mitophagy; parkin
    DOI:  https://doi.org/10.1080/15548627.2022.2038501
  3. Circulation. 2022 Mar 03.
    Heteroplasmy of Wild Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.
    Ana Victoria Lechuga-Vieco, Ana Latorre-Pellicer, Enrique Calvo, Carlos Torroja, Juan Pellico, Rebeca Acín-Pérez, María Luisa García-Gil, Arnoldo Santos, Navratan Bagwan, Elena Bonzon-Kulichenko, Ricardo Magni, Marina Benito, Raquel Justo-Méndez, Anna Katharina Simon, Fátima Sánchez-Cabo, Jesús Vázquez, Jesús Ruíz-Cabello, José Antonio Enríquez.
      Background: In most eukaryotic cells, the mitochondrial DNA (mtDNA) is uniparentally transmitted and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of more than one mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent non-pathological mtDNAs heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. Methods: We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiological and phenotyping techniques. We focused on in vivo imaging techniques for non-invasive assessment of cardiac and pulmonary energy metabolism. Results: We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Conclusions: Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.121.056286
  4. Trends Cell Biol. 2022 Feb 24. pii: S0962-8924(22)00034-4. [Epub ahead of print]
    Long-lived mitochondrial proteins and why they exist.
    Ewa Bomba-Warczak, Jeffrey N Savas.
      Intracellular long-lived proteins (LLPs) provide structural support for several highly stable protein complexes and assemblies that play essential roles in ensuring cellular homeostasis and function. Recently, mitochondrial long-lived proteins (mt-LLPs) were discovered within inner mitochondria membranes (IMMs) and cristae invagination in tissues with old postmitotic cells. This observation is at odds with the fact that mitochondria are highly dynamic organelles that are continually remodeled through processes of fission, fusion, biogenesis, and multiple quality control pathways. In this opinion article, we propose that a subset of the mitochondrial proteome persists over long time frames and these mt-LLPs provide key structural support for the lifelong maintenance of mitochondrial structure.
    Keywords:  cristae ultrastructure; long-lived proteins; mitochondria; mitochondrial dynamics; protein turnover; stable structures
    DOI:  https://doi.org/10.1016/j.tcb.2022.02.001
  5. Int J Legal Med. 2022 Mar 04.
    Exploring statistical weight estimates for mitochondrial DNA matches involving heteroplasmy.
    Jennifer A McElhoe, Peter R Wilton, Walther Parson, Mitchell M Holland.
      Massively parallel sequencing (MPS) of mitochondrial (mt) DNA allows forensic laboratories to report heteroplasmy on a routine basis. Statistical approaches will be needed to determine the relative frequency of observing an mtDNA haplotype when including the presence of a heteroplasmic site. Here, we examined 1301 control region (CR) sequences, collected from individuals in four major population groups (European, African, Asian, and Latino), and covering 24 geographically distributed haplogroups, to assess the rates of point heteroplasmy (PHP) on an individual and nucleotide position (np) basis. With a minor allele frequency (MAF) threshold of 2%, the data was similar across population groups, with an overall PHP rate of 37.7%, and the majority of heteroplasmic individuals (77.3%) having only one site of heteroplasmy. The majority (75.2%) of identified PHPs had an MAF of 2-10%, and were observed at 12.6% of the nps across the CR. Both the broad and phylogenetic testing suggested that in many cases the low number of observations of heteroplasmy at any one np results in a lack of statistical association. The posterior frequency estimates, which skew conservative to a degree depending on the sample size in a given haplogroup, had a mean of 0.152 (SD 0.134) and ranged from 0.031 to 0.83. As expected, posterior frequency estimates decreased in accordance with 1/n as the sample size (n) increased. This provides a proposed conservative statistical framework for assessing haplotype/heteroplasmy matches when applying an MPS technique in forensic cases and will allow for continual refinement as more data is generated, both within the CR and across the mitochondrial genome.
    Keywords:  Control region; Forensic mtDNA; Forensic statistics; Massively parallel sequencing; MiSeq; Rates of mtDNA heteroplasmy
    DOI:  https://doi.org/10.1007/s00414-022-02774-5
  6. Mitochondrion. 2022 Feb 24. pii: S1567-7249(22)00019-8. [Epub ahead of print]64 45-58
    Mitochondrial ribosomal protein genes connected with Alzheimer's and tellurite toxicity.
    Luigi Del Giudice, Pietro Alifano, Matteo Calcagnile, Elia Di Schiavi, Carla Bertapelle, Mariarosaria Aletta, Paola Pontieri.
      Mitochondrial diseases are a group of genetic disorders characterized by dysfunctional mitochondria. Within eukaryotic cells, mitochondria contain their own ribosomes, which synthesize small amounts of proteins, all of which are essential for the biogenesis of the oxidative phosphorylation system. The ribosome is an evolutionarily conserved macromolecular machine in nature both from a structural and functional point of view, universally responsible for the synthesis of proteins. Among the diseases afflicting humans, those of ribosomal origin - either cytoplasmic ribosomes (80S) or mitochondrial ribosomes (70S) - are relevant. These are inherited or acquired diseases most commonly caused by either ribosomal protein haploinsufficiency or defects in ribosome biogenesis. Here we review the scientific literature about the recent advances on changes in mitochondrial ribosomal structural and assembly proteins that are implicated in primary mitochondrial diseases and neurodegenerative disorders, and their possible connection with metalloid pollution and toxicity, with a focus on MRPL44, NAM9 (MNA6) and GEP3 (MTG3), whose lack or defect was associated with resistance to tellurite. Finally, we illustrate the suitability of yeast Saccharomyces cerevisiae (S. cerevisiae) and the nematode Caenorhabditis elegans (C. elegans) as model organisms for studying mitochondrial ribosome dysfunctions including those involved in human diseases.
    Keywords:  Alzheimer’s disease; Mitochondrial diseases; Mitochondrial ribosomal protein genes; Mitochondrial ribosome; Yeast and C. elegans model organisms
    DOI:  https://doi.org/10.1016/j.mito.2022.02.006
  7. Front Cell Dev Biol. 2022 ;10 796066
    Role of Mitochondrial Nucleic Acid Sensing Pathways in Health and Patho-Physiology.
    Arpita Chowdhury, Steffen Witte, Abhishek Aich.
      Mitochondria, in symbiosis with the host cell, carry out a wide variety of functions from generating energy, regulating the metabolic processes, cell death to inflammation. The most prominent function of mitochondria relies on the oxidative phosphorylation (OXPHOS) system. OXPHOS heavily influences the mitochondrial-nuclear communication through a plethora of interconnected signaling pathways. Additionally, owing to the bacterial ancestry, mitochondria also harbor a large number of Damage Associated Molecular Patterns (DAMPs). These molecules relay the information about the state of the mitochondrial health and dysfunction to the innate immune system. Consequently, depending on the intracellular or extracellular nature of detection, different inflammatory pathways are elicited. One group of DAMPs, the mitochondrial nucleic acids, hijack the antiviral DNA or RNA sensing mechanisms such as the cGAS/STING and RIG-1/MAVS pathways. A pro-inflammatory response is invoked by these signals predominantly through type I interferon (T1-IFN) cytokines. This affects a wide range of organ systems which exhibit clinical presentations of auto-immune disorders. Interestingly, tumor cells too, have devised ingenious ways to use the mitochondrial DNA mediated cGAS-STING-IRF3 response to promote neoplastic transformations and develop tumor micro-environments. Thus, mitochondrial nucleic acid-sensing pathways are fundamental in understanding the source and nature of disease initiation and development. Apart from the pathological interest, recent studies also attempt to delineate the structural considerations for the release of nucleic acids across the mitochondrial membranes. Hence, this review presents a comprehensive overview of the different aspects of mitochondrial nucleic acid-sensing. It attempts to summarize the nature of the molecular patterns involved, their release and recognition in the cytoplasm and signaling. Finally, a major emphasis is given to elaborate the resulting patho-physiologies.
    Keywords:  disease; innate immunity; mitochondrial—nuclear exchange; mitochondrion; signaling
    DOI:  https://doi.org/10.3389/fcell.2022.796066
  8. Neurochem Res. 2022 Feb 26.
    Mitochondrial Sirtuins in Parkinson's Disease.
    Ling He, Jihong Wang, Yazhi Yang, Jian Li, Huaijun Tu.
      Parkinson's disease (PD), the main risk factor for which is age, is one of the most common neurodegenerative diseases and imposes a substantial burden on affected individuals and the economy. While the aetiology of PD is still largely unclear, substantial evidence indicates that mitochondrial dysfunction, aggregation of α-synuclein (α-syn), oxidative stress, inflammation, and autophagy play major roles in the pathogenesis of PD. Sirtuins are NAD+-dependent protein deacetylases, includeing seven members, i.e., SIRT1-SIRT7. Among these sirtuins, SIRT3, SIRT4 and SIRT5 are located in mitochondria and are called mitochondrial sirtuins. Mitochondrial sirtuins regulate the activity and biological function of mitochondrial proteins through posttranslational modification of substrate proteins. Increasing evidence shows that mitochondrial sirtuins play an important role in degenerative diseases, including PD. Mitochondrial sirtuins exert a beneficial neuroprotective effect in various models of PD. This paper summarizes a large number of studies and discusses the latest research progress on the role of mitochondrial sirtuins in PD, focusing especially on the regulation of the mitochondrial respiratory chain (MRC), oxidative stress, the inflammatory response and autophagy, to provide new insight into the pathogenesis of PD and new targets for the diagnosis and treatment of the disease.
    Keywords:  Autophagy; Inflammation; Mitochondrial respiratory chain; Mitochondrial sirtuins; PD; ROS
    DOI:  https://doi.org/10.1007/s11064-022-03560-w
  9. Sci Transl Med. 2022 Mar 02. 14(634): eabl6992
    SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA.
    Hezhi Fang, Anran Xie, Miaomiao Du, Xueyun Li, Kaiqiang Yang, Yinxu Fu, Xiangshu Yuan, Runxiao Fan, Weidong Yu, Zhuohua Zhou, Tiantian Sang, Ke Nie, Jin Li, Qiongya Zhao, Zhehui Chen, Yanling Yang, Chaoyang Hong, Jianxin Lyu.
      SERAC1 deficiency is associated with the mitochondrial 3-methylglutaconic aciduria with deafness, (hepatopathy), encephalopathy, and Leigh-like disease [MEGD(H)EL] syndrome, but the role of SERAC1 in mitochondrial physiology remains unknown. Here, we generated Serac1-/- mice that mimic the major diagnostic clinical and biochemical phenotypes of the MEGD(H)EL syndrome. We found that SERAC1 localizes to the outer mitochondrial membrane and is a protein component of the one-carbon cycle. By interacting with the mitochondrial serine transporter protein SFXN1, SERAC1 facilitated and was required for SFXN1-mediated serine transport from the cytosol to the mitochondria. Loss of SERAC1 impaired the one-carbon cycle and disrupted the balance of the nucleotide pool, which led to primary mitochondrial DNA (mtDNA) depletion in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides. Moreover, both in vitro and in vivo supplementation of nucleosides/nucleotides restored mtDNA content and mitochondrial function. Collectively, our findings suggest that MEGD(H)EL syndrome shares both clinical and molecular features with the mtDNA depletion syndrome, and nucleotide supplementation may be an effective therapeutic strategy for MEGD(H)EL syndrome.
    DOI:  https://doi.org/10.1126/scitranslmed.abl6992
  10. bioRxiv. 2022 Feb 22. pii: 2022.02.19.481089. [Epub ahead of print]
    Targeted Down Regulation Of Core Mitochondrial Genes During SARS-CoV-2 Infection.
    Joseph W Guarnieri, Joseph M Dybas, Hossein Fazelinia, Man S Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G Murdock, Alessia Angelin, Larry N Singh, Scott L Weiss, Sonja M Best, Marie T Lott, Henry Cope, Viktorija Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yared H Kidane, Waldemar Priebe, Mark R Emmett, Robert Meller, Urminder Singh, Yaron Bram, Benjamin R tenOever, Mark T Heise, Nathaniel J Moorman, Emily A Madden, Sharon A Taft-Benz, Elizabeth J Anderson, Wes A Sanders, Rebekah J Dickmander, Victoria K Baxter, Stephen B Baylin, Eve Syrkin Wurtele, Pedro M Moraes-Vieira, Deanne Taylor, Christopher E Mason, Jonathan C Schisler, Robert E Schwartz, Afshin Beheshti, Douglas C Wallace.
      Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19.One-Sentence Summary: Covid-19 is associated with targeted inhibition of mitochondrial gene transcription.
    DOI:  https://doi.org/10.1101/2022.02.19.481089
  11. J Neurol. 2022 Mar 02.
    Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes.
    Yu Hiramatsu, Yuji Okamoto, Akiko Yoshimura, Jun-Hui Yuan, Masahiro Ando, Yujiro Higuchi, Akihiro Hashiguchi, Eiji Matsuura, Fumihito Nozaki, Tomohiro Kumada, Kei Murayama, Mikiya Suzuki, Yuki Yamamoto, Naoko Matsui, Yoshimichi Miyazaki, Masamitsu Yamaguchi, Youji Suzuki, Jun Mitsui, Hiroyuki Ishiura, Masaki Tanaka, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroshi Takashima.
      Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.
    Keywords:  Mitochondrial disease; Nuclear genes; Peripheral neuropathy; Whole-exome sequencing
    DOI:  https://doi.org/10.1007/s00415-022-11026-w
  12. Trends Immunol. 2022 Feb 11. pii: S1471-4906(22)00025-4. [Epub ahead of print]
    NAD+ in COVID-19 and viral infections.
    Minyan Zheng, Michael B Schultz, David A Sinclair.
      NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD+ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD+ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD+-mediated actions via genes that remove NAD+ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD+ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation.
    Keywords:  COVID-19; NAD(+); immune responses; inflammation
    DOI:  https://doi.org/10.1016/j.it.2022.02.001
  13. Development. 2022 Mar 03. pii: dev.200458. [Epub ahead of print]
    LONP1-mediated mitochondrial quality control safeguards metabolic shifts in heart development.
    Ke Zhao, Xinyi Huang, Wukui Zhao, Bin Lu, Zhongzhou Yang.
      The mitochondrial matrix AAA+ Lon protease (LONP1) degrades misfolded or unassembled proteins, which play a pivotal role in mitochondrial quality control. During heart development, a metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation takes place, and this process relies highly on functional mitochondria. However, the relationship between mitochondrial quality control machinery and metabolic shifts is elusive. Here, we interfered with mitochondrial quality control by inactivating Lonp1 in embryonic cardiac tissue and found severely impaired heart development, leading to embryonic lethality. Mitochondrial swelling, cristae loss and abnormal protein aggregates were evident in the mitochondria of Lonp1-deficient cardiomyocytes. Accordingly, the p-eIF2α-ATF4 pathway was triggered, and nuclear translocation of ATF4 was observed. We further demonstrated that ATF4 negatively regulates the expression of Tfam while promoting that of Glut1, which was responsible for the disruption of the metabolic shift to oxidative phosphorylation. Meanwhile, elevated levels of reactive oxygen species were observed in Lonp1 mutant cardiomyocytes. This study revealed that LONP1 safeguards metabolic shifts in the developing heart by controlling mitochondrial protein quality and implies that disrupted mitochondrial quality control may cause prenatal cardiomyopathy.
    Keywords:  ATF4; Glycolysis; Heart development; LONP1; Metabolic shift; Mitochondrial quality control; Oxidative phosphorylation
    DOI:  https://doi.org/10.1242/dev.200458
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