bims-mitmed 2024-02-18 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–02–18
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.
Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.
Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
The HRI branch of the integrated stress response selectively triggers mitophagy.
AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia.
Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.
Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
The role of mitophagy in metabolic diseases and its exercise intervention.
Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.
Renal aging and mitochondrial quality control.
A Japanese Case of Leber's Hereditary Optic Neuropathy with the m.13051G>A Pathogenic Variant.
Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
Mitochondrial Calcium Transport During Autophagy Initiation.
A single-cell time-lapse of mouse prenatal development from gastrula to birth.
A system for inducible mitochondria-specific protein degradation in vivo.
A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
Overarching pathomechanisms in inherited peripheral neuropathies, spastic paraplegias, and cerebellar ataxias.
Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
Did mitophagy follow the origin of mitochondria?
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.
Determining the potency of primordial germ cells by injection into early mouse embryos.
SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
Ceramides and mitochondrial homeostasis.

Nat Commun. 2024 Feb 10. 15(1): 1252

Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.

Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.

Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.

DOI: https://doi.org/10.1038/s41467-024-45651-y
BMJ Neurol Open. 2024 ;6(1): e000546

Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.

Mika H Martikainen, Kari Majamaa.

   Background: Mitochondrial diseases are common inherited metabolic disorders. Due to improved case ascertainment and diagnosis methods, the detection of new diagnoses of mitochondrial disease can be expected to increase. In December 2009, the prevalence of mitochondrial DNA (mtDNA)-related mitochondrial disease was 4.6/100 000 (95% CI, 2.7 to 7.2) in the adult population of Southwest Finland. We investigated the number of new diagnoses and the incidence of mitochondrial disease in Southwest Finland between December 2009 and December 2022.
Methods: We collected data on all adult patients from Southwest Finland diagnosed with mitochondrial disease on 31 December 2009 and 31 December 2022. Most patients had been diagnosed at the Turku University Hospital (TUH) neurology outpatient clinic. Patients were also identified by searching the TUH electronic patient database for relevant International Classification of Diseases, Tenth Revision codes and conducted mtDNA analyses.
Results: 42 new patients were diagnosed giving a mean annual rate of 3.2 new diagnoses. In 2022, the minimum prevalence estimate of adult mtDNA-related mitochondrial disease was 9.2/100 000 (95% CI, 6.5 to 12.7). The prevalence of adult mtDNA disease associated with m.3243A>G was 4.2/100 000 (95% CI, 2.5 to 6.7), and that with large-scale mtDNA deletions was 1.3/100 000 (95% CI, 0.4 to 2.9). During the 13-year period, the annual incidence of adult mtDNA disease was 0.6/100 000 and that of adult m.3243A>G-related disease 0.3/100 000.
Conclusion: Our results suggest that improved means of diagnostics and dedicated effort increase the detection of mitochondrial disease.

Keywords:  MITOCHONDRIAL DISORDERS; NEUROEPIDEMIOLOGY

DOI:  https://doi.org/10.1136/bmjno-2023-000546
Paediatr Anaesth. 2024 Feb 15.

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.

Kira A Spencer, Miranda N Howe, Michael T Mulholland, Vivian Truong, Ryan W Liao, Yihan Chen, Monyreak Setha, John C Snell, Allison Hanaford, Katerina James, Philip G Morgan, Margaret M Sedensky, Simon C Johnson.

   BACKGROUND: Genetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting in infancy or early childhood. Seizures are major clinical sequelae in some mitochondrial diseases including Leigh syndrome, the most common pediatric presentation of mitochondrial disease. Dietary ketosis has been used to manage seizures in mitochondrial disease patients. Mitochondrial disease patients often require surgical interventions, leading to anesthetic exposures. Anesthetics have been shown to be toxic in the setting of mitochondrial disease, but the impact of a ketogenic diet on anesthetic toxicities in this setting has not been studied.
AIMS: Our aim in this study was to determine whether dietary ketosis impacts volatile anesthetic toxicities in the setting of genetic mitochondrial disease.
METHODS: The impact of dietary ketosis on toxicities of volatile anesthetic exposure in mitochondrial disease was studied by exposing young Ndufs4(-/-) mice fed ketogenic or control diet to isoflurane anesthesia. Blood metabolites were measured before and at the end of exposures, and survival and weight were monitored.
RESULTS: Compared to a regular diet, the ketogenic diet exacerbated hyperlactatemia resulting from isoflurane exposure (control vs. ketogenic diet in anesthesia mean difference 1.96 mM, Tukey's multiple comparison adjusted p = .0271) and was associated with a significant increase in mortality during and immediately after exposures (27% vs. 87.5% mortality in the control and ketogenic diet groups, respectively, during the exposure period, Fisher's exact test p = .0121). Our data indicate that dietary ketosis and volatile anesthesia interact negatively in the setting of mitochondrial disease.
CONCLUSIONS: Our findings suggest that extra caution should be taken in the anesthetic management of mitochondrial disease patients in dietary ketosis.

Keywords:  anesthesia; ketogenic diet; mitochondrial disease; neurodegenerative disease

DOI:  https://doi.org/10.1111/pan.14855
Nat Struct Mol Biol. 2024 Feb 12.

Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.

R Stefan Isaac, Thomas W Tullius, Katja G Hansen, Danilo Dubocanin, Mary Couvillion, Andrew B Stergachis, L Stirling Churchman.

Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.

DOI: https://doi.org/10.1038/s41594-024-01225-6
Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]

The HRI branch of the integrated stress response selectively triggers mitophagy.

Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.

  To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.

Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control

DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
Mol Ther Methods Clin Dev. 2024 Mar 14. 32(1): 101193

AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia.

Joshua C Chang, Molly R Ryan, Marie C Stark, Su Liu, Pravinkumar Purushothaman, Fria Bolan, Caitlin A Johnson, Mark Champe, Hui Meng, Michael W Lawlor, Sarah Halawani, Lucie V Ngaba, David R Lynch, Crystal Davis, Elena Gonzalo-Gil, Cathleen Lutz, Fabrizia Urbinati, Bala Medicherla, Carlos Fonck.

  Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

Keywords:  AAV; Friedreich’s ataxia; PGK; adeno-associated viral vector; cardiomyopathy; frataxin; gene therapy; phosphoglycerate kinase; promoter

DOI:  https://doi.org/10.1016/j.omtm.2024.101193
Development. 2024 Feb 12. pii: dev.201732. [Epub ahead of print]

Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.

Bhavin Uttekar, Rahul Kumar Verma, Darshika Tomer, Richa Rikhy.

  Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells in Drosophila oogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1 depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. These defects are suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2, and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2, and catalase partially restores the defects in epithelial polarity and aPKC, along with EGFR and Notch signaling in Drp1 depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation, and epithelial cell polarity formation during the differentiation of follicle epithelial cells in Drosophila oogenesis.

Keywords:   Drosophila ; APKC; Drp1; Epithelial polarity; Mitochondria; Opa1; ROS

DOI:  https://doi.org/10.1242/dev.201732
Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738

Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.

Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.

  Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.

Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence

DOI:  https://doi.org/10.1016/j.celrep.2024.113738
Front Physiol. 2024 ;15 1339128

The role of mitophagy in metabolic diseases and its exercise intervention.

Shaokai Tang, Yuanwen Geng, Qinqin Lin.

  Mitochondria are energy factories that sustain life activities in the body, and their dysfunction can cause various metabolic diseases that threaten human health. Mitophagy, an essential intracellular mitochondrial quality control mechanism, can maintain cellular and metabolic homeostasis by removing damaged mitochondria and participating in developing metabolic diseases. Research has confirmed that exercise can regulate mitophagy levels, thereby exerting protective metabolic effects in metabolic diseases. This article reviews the role of mitophagy in metabolic diseases, the effects of exercise on mitophagy, and the potential mechanisms of exercise-regulated mitophagy intervention in metabolic diseases, providing new insights for future basic and clinical research on exercise interventions to prevent and treat metabolic diseases.

Keywords:  exercise; exerkine; metabolic disease; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.3389/fphys.2024.1339128
Nefrologia (Engl Ed). 2023 Dec;pii: S2013-2514(24)00027-0. [Epub ahead of print]43 Suppl 2 1-7

Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.

Filipa Ferreira, Clara Gonçalves Bacelar, Pedro Lisboa-Gonçalves, Núria Paulo, Rita Quental, Ana Teresa Nunes, Roberto Silva, Isabel Tavares.

  Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.

Keywords:  Enfermedades mitocondriales; Enfermedades renales; Focal segmental glomerulosclerosis; Glomeruloesclerosis focal y segmentaria; MELAS syndrome; Mitochondrial diseases; Renal disease; Síndrome MELAS; mtDNA m.3243A>G

DOI:  https://doi.org/10.1016/j.nefroe.2024.01.017
Biogerontology. 2024 Feb 13.

Renal aging and mitochondrial quality control.

Xiuli Guo, Jiao Wang, Yinjie Wu, Xinwang Zhu, Li Xu.

  Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.

Keywords:  Aging; Mitochondrial dysfunction; Mitochondrial quality control; Renal intrinsic cells

DOI:  https://doi.org/10.1007/s10522-023-10091-6
Neuroophthalmology. 2024 ;48(1): 51-55

A Japanese Case of Leber's Hereditary Optic Neuropathy with the m.13051G>A Pathogenic Variant.

Yasuyuki Takai, Mayumi Iwasa, Akiko Yamagami, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.

  Leber's hereditary optic neuropathy (LHON) is one of the hereditary optic neuropathies and is principally caused by three frequent mitochondria deoxyribonucleic acid (DNA) pathogenic variants (m.11778 G>A, m.3460 G>A, and m.14484T>C). These pathogenic variants account for 90% of LHON cases, with rare pathogenic variants accounting for the remaining cases. We report the first Japanese case of LHON with the m.13051 G>A pathogenic variant, which is a rare primary pathogenic variant of LHON. A 24-year-old woman developed subacute visual loss in both eyes over several months. The best corrected visual acuity (BCVA) was 6/120 in her right eye (OD) and 6/7.5 in her left eye (OS). A relative afferent pupillary defect was not detected. Humphrey visual field testing revealed a central scotoma OD and a temporal paracentral scotoma OS. Fundus examination showed the presence of a pale optic disc OD and optic disc swelling with peripapillary microangiopathy OS. Orbital magnetic resonance imaging showed no abnormal findings. As the mitochondrial DNA gene testing demonstrated the m.13051 G>A pathogenic variant, the patient was diagnosed with LHON. Subsequently, her BCVA worsened to 6/600 in each eye, followed by a nearly plateau-like progression thereafter. This mutation has been primarily reported in Europe but has not yet been confirmed in the Asian region. This case also indicates the importance of examining the whole mitochondrial DNA gene for pathogenic variants in cases where one of the three major pathogenic variants has not been not detected.

Keywords:  Leber’s hereditary optic neuropathy; genetic testing; m.13051G>A pathogenic variant; mitochondrial disease; optic neuropathy

DOI:  https://doi.org/10.1080/01658107.2023.2273480
Nat Ecol Evol. 2024 Feb 15.

Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.

Isabel M Serrano, Misa Hirose, Charles C Valentine, Sharon Roesner, Elizabeth Schmidt, Gabriel Pratt, Lindsey Williams, Jesse Salk, Saleh Ibrahim, Peter H Sudmant.

Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that 're-align' mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.

DOI: https://doi.org/10.1038/s41559-024-02338-3
Aging Cell. 2024 Feb 15. e14103

Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.

Tse Yu Chen, Feng-Yung Wang, Pin-Jung Lee, Ao-Lin Hsu, Tsui-Ting Ching.

  S-adenosylmethionine (SAM), generated from methionine and ATP by S-adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams-1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt ) and lifespan extension. In this study, we found that depleting SAMS-1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC-25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt , suggesting that the UPRmt induced by sams-1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT-10C.2 as a major downstream effector of SAMS-1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS-1 regulates UPRmt and longevity.

Keywords:  S-adenosyl methionine; UPRmt; longevity; mitochondrial tRNA methyltransferase

DOI:  https://doi.org/10.1111/acel.14103
Mitochondrial Commun. 2024 ;2 14-20

Mitochondrial Calcium Transport During Autophagy Initiation.

Sujyoti Chandra, Parul Katiyar, Aarooran S Durairaj, Xinnan Wang.

  While it has been shown that Ca2+ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca2+ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca2+ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca2+ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca2+ transport and Ca2+ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca2+ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca2+ influx is faster, which may slow the ensuing mitophagy.

Keywords:  ER Ca2+ transient; IP3R; MCU; Parkinson; RyR; autophagy; mitochondrial Ca2+ uptake; mitophagy

DOI:  https://doi.org/10.1016/j.mitoco.2024.01.002
Nature. 2024 Feb 14.

A single-cell time-lapse of mouse prenatal development from gastrula to birth.

Chengxiang Qiu, Beth K Martin, Ian C Welsh, Riza M Daza, Truc-Mai Le, Xingfan Huang, Eva K Nichols, Megan L Taylor, Olivia Fulton, Diana R O'Day, Anne Roshella Gomes, Saskia Ilcisin, Sanjay Srivatsan, Xinxian Deng, Christine M Disteche, William Stafford Noble, Nobuhiko Hamazaki, Cecilia B Moens, David Kimelman, Junyue Cao, Alexander F Schier, Malte Spielmann, Stephen A Murray, Cole Trapnell, Jay Shendure.

The house mouse (Mus musculus) is an exceptional model system, combining genetic tractability with close evolutionary affinity to humans1,2. Mouse gestation lasts only 3 weeks, during which the genome orchestrates the astonishing transformation of a single-cell zygote into a free-living pup composed of more than 500 million cells. Here, to establish a global framework for exploring mammalian development, we applied optimized single-cell combinatorial indexing3 to profile the transcriptional states of 12.4 million nuclei from 83 embryos, precisely staged at 2- to 6-hour intervals spanning late gastrulation (embryonic day 8) to birth (postnatal day 0). From these data, we annotate hundreds of cell types and explore the ontogenesis of the posterior embryo during somitogenesis and of kidney, mesenchyme, retina and early neurons. We leverage the temporal resolution and sampling depth of these whole-embryo snapshots, together with published data4-8 from earlier timepoints, to construct a rooted tree of cell-type relationships that spans the entirety of prenatal development, from zygote to birth. Throughout this tree, we systematically nominate genes encoding transcription factors and other proteins as candidate drivers of the in vivo differentiation of hundreds of cell types. Remarkably, the most marked temporal shifts in cell states are observed within one hour of birth and presumably underlie the massive physiological adaptations that must accompany the successful transition of a mammalian fetus to life outside the womb.

DOI: https://doi.org/10.1038/s41586-024-07069-w
Nat Commun. 2024 Feb 16. 15(1): 1454

A system for inducible mitochondria-specific protein degradation in vivo.

Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.

Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.

DOI: https://doi.org/10.1038/s41467-024-45819-6
Nat Neurosci. 2024 Feb 15.

A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.

Paula R Haynes, Elana S Pyfrom, Yongjun Li, Carly Stein, Vishnu Anand Cuddapah, Jack A Jacobs, Zhifeng Yue, Amita Sehgal.

Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.

DOI: https://doi.org/10.1038/s41593-023-01568-1
Nat Commun. 2024 Feb 13. 15(1): 1328

Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.

Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.

Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

DOI: https://doi.org/10.1038/s41467-024-45524-4
Trends Neurosci. 2024 Feb 14. pii: S0166-2236(24)00016-X. [Epub ahead of print]

Overarching pathomechanisms in inherited peripheral neuropathies, spastic paraplegias, and cerebellar ataxias.

Liedewei Van de Vondel, Jonathan De Winter, Vincent Timmerman, Jonathan Baets.

  International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development. We highlight common cellular alterations that underlie this genetic landscape, including alteration of cytoskeleton, axonal transport, mitochondrial function, and DNA repair response. Finally, we discuss venues for future research using the long axonopathies of the PNS as a model to explore other neurogenetic disorders.

Keywords:  DNA integrity and gene expression; axonal transport; ion channels; mitochondria and metabolism; neurogenetic disease; protein quality control

DOI:  https://doi.org/10.1016/j.tins.2024.01.004
FEBS J. 2024 Feb 16.

Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.

Ilaria Goglia, Ewelina Węglarz-Tomczak, Claudio Gioia, Yanhua Liu, Assunta Virtuoso, Marcella Bonanomi, Daniela Gaglio, Noemi Salmistraro, Ciro De Luca, Michele Papa, Lilia Alberghina, Hans V Westerhoff, Anna Maria Colangelo.

  Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.

Keywords:  NGF differentiation; computational modeling; metabolism; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1111/febs.17083
Autophagy. 2024 Feb 15. 1-9

Did mitophagy follow the origin of mitochondria?

Mauro Degli Esposti.

  Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. Mitophagy was first characterized in mammalian cells and is now recognized to follow several pathways including basal forms in specific organs. Mitophagy pathways are regulated by multiple, often interconnected factors. The present review aims to streamline this complexity and evaluate common elements that may define the evolutionary origin of mitophagy. Key issues surrounding mitophagy signaling at the mitochondrial surface may fundamentally derive from mitochondrial membrane dynamics. Elements of such membrane dynamics likely originated during the endosymbiosis of the alphaproteobacterial ancestor of our mitochondria but underwent an evolutionary leap forward in basal metazoa that determined the currently known variations in mitophagy signaling.Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; ATG, autophagy related; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CALCOCO, calcium binding and coiled-coil domain; CL, cardiolipin; ER, endoplasmic reticulum; ERMES, ER-mitochondria encounter structure; FBXL4, F-box and leucine rich repeat protein 4; FUNDC1, FUN14 domain containing 1; GABARAPL1, GABA type A receptor associated protein like 1; HIF, hypoxia inducible factor; IMM, inner mitochondrial membrane; LBPA/BMP, lysobisphosphatidic acid; LIR, LC3-interacting region; LPA, lysophosphatidic acid; MAM, mitochondria-associated membranes; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MCL, monolysocardiolipin; ML, maximum likelihood; NBR1, NBR1 autophagy cargo receptor; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PACS2, phosphofurin acidic cluster sorting protein 2; PC/PLC, phosphatidylcholine; PE, phosphatidylethanolamine; PHB2, prohibitin 2; PINK1, PTEN induced kinase 1; PtdIns, phosphatidylinositol; SAR, Stramenopiles, Apicomplexa and Rhizaria; TAX1BP1, Tax1 binding protein 1; ULK1, unc-51 like autophagy activating kinase 1; VDAC/porin, voltage dependent anion channel.

Keywords:  BNIP3; cardiolipin; evolution; membrane dynamics; mitochondria; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2307215
J Clin Invest. 2024 Feb 15. pii: e174824. [Epub ahead of print]134(4):

A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Justin O Szot, Hartmut Cuny, Ella Mma Martin, Delicia Z Sheng, Kavitha Iyer, Stephanie Portelli, Vivien Nguyen, Jessica M Gereis, Dimuthu Alankarage, David Chitayat, Karen Chong, Ingrid M Wentzensen, Catherine Vincent-Delormé, Alban Lermine, Emma Burkitt-Wright, Weizhen Ji, Lauren Jeffries, Lynn S Pais, Tiong Y Tan, James Pitt, Cheryl A Wise, Helen Wright, Israel D Andrews, Brianna Pruniski, Theresa A Grebe, Nicole Corsten-Janssen, Katelijne Bouman, Cathryn Poulton, Supraja Prakash, Boris Keren, Natasha J Brown, Matthew F Hunter, Oliver Heath, Saquib A Lakhani, John H McDermott, David B Ascher, Gavin Chapman, Kayleigh Bozon, Sally L Dunwoodie.

  Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Keywords:  Embryonic development; Genetic diseases; Mouse models; Reproductive biology; Therapeutics

DOI:  https://doi.org/10.1172/JCI174824
Dev Cell. 2024 Feb 09. pii: S1534-5807(24)00042-X. [Epub ahead of print]

Determining the potency of primordial germ cells by injection into early mouse embryos.

Lessly P Sepulveda-Rincon, Yi-Fang Wang, Chad Whilding, Benjamin Moyon, Obah A Ojarikre, Valdone Maciulyte, Nobuhiko Hamazaki, Katsuhiko Hayashi, James M A Turner, Harry G Leitch.

  Primordial germ cells (PGCs) are the earliest precursors of the gametes. During normal development, PGCs only give rise to oocytes or spermatozoa. However, PGCs can acquire pluripotency in vitro by forming embryonic germ (EG) cells and in vivo during teratocarcinogenesis. Classic embryological experiments directly assessed the potency of PGCs by injection into the pre-implantation embryo. As no contribution to embryos or adult mice was observed, PGCs have been described as unipotent. Here, we demonstrate that PGCs injected into 8-cell embryos can initially survive, divide, and contribute to the developing inner cell mass. Apoptosis-deficient PGCs exhibit improved survival in isolated epiblasts and can form naive pluripotent embryonic stem cell lines. However, contribution to the post-implantation embryo is limited, with no functional incorporation observed. In contrast, PGC-like cells show an extensive contribution to mid-gestation chimeras. We thus propose that PGC formation in vivo establishes a latent form of pluripotency that restricts chimera contribution.

Keywords:  embryonic stem cells; germ line; pluripotency; primordial germ cell-like cells; primordial germ cells

DOI:  https://doi.org/10.1016/j.devcel.2024.01.022
Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]

SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.

Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.

  SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.

Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism

DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
Cell Signal. 2024 Feb 13. pii: S0898-6568(24)00067-6. [Epub ahead of print] 111099

Ceramides and mitochondrial homeostasis.

Song Ding, Guorui Li, Tinglv Fu, Tianyu Zhang, Xiao Lu, Ning Li, Qing Geng.

  Lipotoxicity arises from the accumulation of lipid intermediates in non-adipose tissue, precipitating cellular dysfunction and death. Ceramide, a toxic byproduct of excessive free fatty acids, has been widely recognized as a primary contributor to lipotoxicity, mediating various cellular processes such as apoptosis, differentiation, senescence, migration, and adhesion. As the hub of lipid metabolism, the excessive accumulation of ceramides inevitably imposes stress on the mitochondria, leading to the disruption of mitochondrial homeostasis, which is typified by adequate ATP production, regulated oxidative stress, an optimal quantity of mitochondria, and controlled mitochondrial quality. Consequently, this review aims to collate current knowledge and facts regarding the involvement of ceramides in mitochondrial energy metabolism and quality control, thereby providing insights for future research.

Keywords:  Ceramide; ETC; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1016/j.cellsig.2024.111099