bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–06–09
eleven papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Senescent glia link mitochondrial dysfunction and lipid accumulation.
  2. Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.
  3. Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
  4. Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
  5. Structural basis for human mitochondrial tRNA maturation.
  6. Structure prediction analysis of human core TIM23 complex reveals conservation of the protein translocation mechanism.
  7. Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.
  8. TRABD modulates mitochondrial homeostasis and tissue integrity.
  9. ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation.
  10. Burkholderia pseudomallei BipD modulates host mitophagy to evade killing.
  11. The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.
  1. Nature. 2024 Jun 05.
    Senescent glia link mitochondrial dysfunction and lipid accumulation.
    China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.
      Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.
    DOI:  https://doi.org/10.1038/s41586-024-07516-8
  2. EMBO J. 2024 Jun 05.
    Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.
    Nanami Senoo, Dinesh K Chinthapalli, Matthew G Baile, Vinaya K Golla, Bodhisattwa Saha, Abraham O Oluwole, Oluwaseun B Ogunbona, James A Saba, Teona Munteanu, Yllka Valdez, Kevin Whited, Macie S Sheridan, Dror Chorev, Nathan N Alder, Eric R May, Carol V Robinson, Steven M Claypool.
      Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS). In the inner mitochondrial membrane, the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) exchanges ADP and ATP, enabling OXPHOS. AAC/ANT contains three tightly bound CLs, and these interactions are evolutionarily conserved. Here, we investigated the role of these buried CLs in AAC/ANT using a combination of biochemical approaches, native mass spectrometry, and molecular dynamics simulations. We introduced negatively charged mutations into each CL-binding site of yeast Aac2 and established experimentally that the mutations disrupted the CL interactions. While all mutations destabilized Aac2 tertiary structure, transport activity was impaired in a binding site-specific manner. Additionally, we determined that a disease-associated missense mutation in one CL-binding site in human ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions.
    Keywords:  Cardiolipin; Lipid–Protein Interaction; Membrane Transport; Mitochondria; Oxidative Phosphorylation
    DOI:  https://doi.org/10.1038/s44318-024-00132-2
  3. Nat Commun. 2024 Jun 03. 15(1): 4700
    Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
    Shashank Dadsena, Rodrigo Cuevas Arenas, Gonçalo Vieira, Susanne Brodesser, Manuel N Melo, Ana J García-Sáez.
      BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.
    DOI:  https://doi.org/10.1038/s41467-024-49067-6
  4. Sci Adv. 2024 Jun 07. 10(23): eadn7191
    Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
    Olawale G Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M Lange, Cristian Polo Rivera, Tom D Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P M Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, Miratul M K Muqit.
      Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.
    DOI:  https://doi.org/10.1126/sciadv.adn7191
  5. Nat Commun. 2024 Jun 01. 15(1): 4683
    Structural basis for human mitochondrial tRNA maturation.
    Vincent Meynier, Steven W Hardwick, Marjorie Catala, Johann J Roske, Stephanie Oerum, Dimitri Y Chirgadze, Pierre Barraud, Wyatt W Yue, Ben F Luisi, Carine Tisné.
      The human mitochondrial genome is transcribed into two RNAs, containing mRNAs, rRNAs and tRNAs, all dedicated to produce essential proteins of the respiratory chain. The precise excision of tRNAs by the mitochondrial endoribonucleases (mt-RNase), P and Z, releases all RNA species from the two RNA transcripts. The tRNAs then undergo 3'-CCA addition. In metazoan mitochondria, RNase P is a multi-enzyme assembly that comprises the endoribonuclease PRORP and a tRNA methyltransferase subcomplex. The requirement for this tRNA methyltransferase subcomplex for mt-RNase P cleavage activity, as well as the mechanisms of pre-tRNA 3'-cleavage and 3'-CCA addition, are still poorly understood. Here, we report cryo-EM structures that visualise four steps of mitochondrial tRNA maturation: 5' and 3' tRNA-end processing, methylation and 3'-CCA addition, and explain the defined sequential order of the tRNA processing steps. The methyltransferase subcomplex recognises the pre-tRNA in a distinct mode that can support tRNA-end processing and 3'-CCA addition, likely resulting from an evolutionary adaptation of mitochondrial tRNA maturation complexes to the structurally-fragile mitochondrial tRNAs. This subcomplex can also ensure a tRNA-folding quality-control checkpoint before the sequential docking of the maturation enzymes. Altogether, our study provides detailed molecular insight into RNA-transcript processing and tRNA maturation in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-024-49132-0
  6. FEBS Open Bio. 2024 Jun 04.
    Structure prediction analysis of human core TIM23 complex reveals conservation of the protein translocation mechanism.
    Klaudia K Maruszczak, Piotr Draczkowski, Artur Wnorowski, Agnieszka Chacinska.
      The majority of mitochondrial proteins are encoded in the nucleus, translated on cytosolic ribosomes, and subsequently targeted to the mitochondrial surface. Their further import into the organelle is facilitated by highly specialized protein translocases. Mitochondrial precursor proteins that are destined to the mitochondrial matrix and, to some extent, the inner membrane, utilize translocase of the inner membrane (TIM23). This indispensable import machinery has been extensively studied in yeast. The translocating unit of the TIM23 complex in yeast consists of two membrane proteins, Tim17 and Tim23. In contrast to previous findings, recent reports demonstrate the primary role of Tim17, rather than Tim23, in the translocation of newly synthesized proteins. Very little is known about human TIM23 translocase. Human cells have two orthologs of yeast Tim17, TIMM17A and TIMM17B. Here, using computational tools, we present the architecture of human core TIM23 variants with either TIMM17A or TIMM17B, forming two populations of highly similar complexes. The structures reveal high conservation of the core TIM23 complex between human and yeast. Interestingly, both TIMM17A and TIMM17B variants interact with TIMM23 and reactive oxygen species modulator 1 (ROMO1); a homolog of yeast Mgr2, a protein that can create a channel-like structure with Tim17. The high structural conservation of proteins that form the core TIM23 complex in yeast and humans raises an interesting question about mechanistic and functional differences that justify existence of the two variants of TIM23 in higher eukaryotes.
    Keywords:  TIM23 complex; TIM23 structure prediction; mitochondria; mitochondrial import
    DOI:  https://doi.org/10.1002/2211-5463.13840
  7. Mol Cell Biol. 2024 Jun 03. 1-19
    Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.
    Jordan J Crameri, Catherine S Palmer, Tegan Stait, Thomas D Jackson, Matthew Lynch, Adriane Sinclair, Leah E Frajman, Alison G Compton, David Coman, David R Thorburn, Ann E Frazier, Diana Stojanovski.
      TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.
    Keywords:  Mitochondria; TIM23 complex; TIMM50; mitochondrial disease; mitochondrial protein import
    DOI:  https://doi.org/10.1080/10985549.2024.2353652
  8. Cell Rep. 2024 Jun 05. pii: S2211-1247(24)00632-6. [Epub ahead of print]43(6): 114304
    TRABD modulates mitochondrial homeostasis and tissue integrity.
    Caixia Zhou, Zhirong Li, Yawen Li, Yaoyao Li, Wei Wang, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      High TRABD expression is associated with tau pathology in patients with Alzheimer's disease; however, the function of TRABD is unknown. Human TRABD encodes a mitochondrial outer-membrane protein. The loss of TRABD resulted in mitochondrial fragmentation, and TRABD overexpression led to mitochondrial clustering and fusion. The C-terminal tail of the TRABD anchored to the mitochondrial outer membrane and the TraB domain could form homocomplexes. Additionally, TRABD forms complexes with MFN2, MIGA2, and PLD6 to facilitate mitochondrial fusion. Flies lacking dTRABD are viable and have normal lifespans. However, aging flies exhibit reduced climbing ability and abnormal mitochondrial morphology in their muscles. The expression of dTRABD is increased in aged flies. dTRABD overexpression leads to neurodegeneration and enhances tau toxicity in fly eyes. The overexpression of dTRABD also increased reactive oxygen species (ROS), ATP production, and protein turnover in the mitochondria. This study suggested that TRABD-induced mitochondrial malfunctions contribute to age-related neurodegeneration.
    Keywords:  CP: Cell biology; Drosophila; mitochondria; mitochondria fusion; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2024.114304
  9. Redox Biol. 2024 May 31. pii: S2213-2317(24)00190-3. [Epub ahead of print]73 103212
    ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation.
    Yena Cho, Yong Kee Kim.
      The dynamic regulation of mitochondria through fission and fusion is essential for maintaining cellular homeostasis. In this study, we discovered a role of coactivator-associated arginine methyltransferase 1 (CARM1) in mitochondrial dynamics. CARM1 methylates specific residues (R403 and R634) on dynamin-related protein 1 (DRP1). Methylated DRP1 interacts with mitochondrial fission factor (Mff) and forms self-assembly on the outer mitochondrial membrane, thereby triggering fission, reducing oxygen consumption, and increasing reactive oxygen species (ROS) production. This sets in motion a feedback loop that facilitates the translocation of CARM1 from the nucleus to the cytoplasm, enhancing DRP1 methylation and ROS production through mitochondrial fragmentation. Consequently, ROS reinforces the CARM1-DRP1-ROS axis, resulting in cellular senescence. Depletion of CARM1 or DRP1 impedes cellular senescence by reducing ROS accumulation. The uncovering of the above-described mechanism fills a missing piece in the vicious cycle of ROS-induced senescence and contributes to a better understanding of the aging process.
    Keywords:  CARM1; DRP1; Methylation; Mitochondrial dynamics; ROS; Senescence
    DOI:  https://doi.org/10.1016/j.redox.2024.103212
  10. Nat Commun. 2024 Jun 04. 15(1): 4740
    Burkholderia pseudomallei BipD modulates host mitophagy to evade killing.
    Dongqi Nan, Chenglong Rao, Zhiheng Tang, Wenbo Yang, Pan Wu, Jiangao Chen, Yupei Xia, Jingmin Yan, Wenzheng Liu, Ziyuan Zhang, Zhiqiang Hu, Hai Chen, Yaling Liao, Xuhu Mao, Xiaoyun Liu, Quanming Zou, Qian Li.
      Mitophagy is critical for mitochondrial quality control and function to clear damaged mitochondria. Here, we found that Burkholderia pseudomallei maneuvered host mitophagy for its intracellular survival through the type III secretion system needle tip protein BipD. We identified BipD, interacting with BTB-containing proteins KLHL9 and KLHL13 by binding to the Back and Kelch domains, recruited NEDD8 family RING E3 ligase CUL3 in response to B. pseudomallei infection. Although evidently not involved in regulation of infectious diseases, KLHL9/KLHL13/CUL3 E3 ligase complex was essential for BipD-dependent ubiquitination of mitochondria in mouse macrophages. Mechanistically, we discovered the inner mitochondrial membrane IMMT via host ubiquitome profiling as a substrate of KLHL9/KLHL13/CUL3 complex. Notably, K63-linked ubiquitination of IMMT K211 was required for initiating host mitophagy, thereby reducing mitochondrial ROS production. Here, we show a unique mechanism used by bacterial pathogens that hijacks host mitophagy for their survival.
    DOI:  https://doi.org/10.1038/s41467-024-48824-x
  11. Proc Natl Acad Sci U S A. 2024 Jun 11. 121(24): e2321267121
    The role of mitochondria in sex- and age-specific gene expression in a species without sex chromosomes.
    Ning Li, Ben A Flanagan, Suzanne Edmands.
      Mitochondria perform an array of functions, many of which involve interactions with gene products encoded by the nucleus. These mitochondrial functions, particularly those involving energy production, can be expected to differ between sexes and across ages. Here, we measured mitochondrial effects on sex- and age-specific gene expression in parental and reciprocal F1 hybrids between allopatric populations of Tigriopus californicus with over 20% mitochondrial DNA divergence. Because the species lacks sex chromosomes, sex-biased mitochondrial effects are not confounded by the effects of sex chromosomes. Results revealed pervasive sex differences in mitochondrial effects, including effects on energetics and aging involving nuclear interactions throughout the genome. Using single-individual RNA sequencing, sex differences were found to explain more than 80% of the variance in gene expression. Males had higher expression of mitochondrial genes and mitochondrially targeted proteins (MTPs) involved in oxidative phosphorylation (OXPHOS), while females had elevated expression of non-OXPHOS MTPs, indicating strongly sex-dimorphic energy metabolism at the whole organism level. Comparison of reciprocal F1 hybrids allowed insights into the nature of mito-nuclear interactions, showing both mitochondrial effects on nuclear expression, and nuclear effects on mitochondrial expression. While based on a small set of crosses, sex-specific increases in mitochondrial expression with age were associated with longer life. Network analyses identified nuclear components of strong mito-nuclear interactions and found them to be sexually dimorphic. These results highlight the profound impact of mitochondria and mito-nuclear interactions on sex- and age-specific gene expression.
    Keywords:  RNA-seq; hybrid; longevity; mitochondria; sex differences
    DOI:  https://doi.org/10.1073/pnas.2321267121
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