bims-mitpro 2024-06-09 papers

Issue of 2024‒06‒09
four papers selected by
Andreas Kohler, Umeå University

bioRxiv. 2024 May 21. pii: 2024.05.20.594820. [Epub ahead of print]

Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism.

James P Held, Nadir H Dbouk, Adrianna M Strozak, Lantana K Grub, Hayeon Ryou, Samantha H Schaffner, Maulik R Patel.

Reproductive status, such as pregnancy and menopause in women, profoundly influences metabolism of the body. Mitochondria likely orchestrate many of these metabolic changes. However, the influence of reproductive status on somatic mitochondria and the underlying mechanisms remain largely unexplored. We demonstrate that reproductive signals modulate mitochondria in the Caenorhabditis elegans soma. We show that the germline acts via an RNA endonuclease, HOE-1, which despite its housekeeping role in tRNA maturation, selectively regulates the mitochondrial unfolded protein response (UPRmt). Mechanistically, we uncover a fatty acid metabolism pathway acting upstream of HOE-1 to convey germline status. Furthermore, we link vitamin B12's dietary intake to the germline's regulatory impact on HOE-1-driven UPRmt. Combined, our study uncovers a germline-somatic mitochondrial connection, reveals the underlying mechanism, and highlights the importance of micronutrients in modulating this connection. Our findings provide insights into the interplay between reproductive biology and metabolic regulation.

DOI: https://doi.org/10.1101/2024.05.20.594820

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

BMC Biol. 2024 Jun 03. 22(1): 130

A hybrid TIM complex mediates protein import into hydrogenosomes of Trichomonas vaginalis.

Abhijith Makki, Sami Kereïche, Tien Le, Jitka Kučerová, Petr Rada, Vojtěch Žárský, Ivan Hrdý, Jan Tachezy.

BACKGROUND: Hydrogenosomes are a specific type of mitochondria that have adapted for life under anaerobiosis. Limited availability of oxygen has resulted in the loss of the membrane-associated respiratory chain, and consequently in the generation of minimal inner membrane potential (Δψ), and inefficient ATP synthesis via substrate-level phosphorylation. The changes in energy metabolism are directly linked with the organelle biogenesis. In mitochondria, proteins are imported across the outer membrane via the Translocase of the Outer Membrane (TOM complex), while two Translocases of the Inner Membrane, TIM22, and TIM23, facilitate import to the inner membrane and matrix. TIM23-mediated steps are entirely dependent on Δψ and ATP hydrolysis, while TIM22 requires only Δψ. The character of the hydrogenosomal inner membrane translocase and the mechanism of translocation is currently unknown.RESULTS: We report unprecedented modification of TIM in hydrogenosomes of the human parasite Trichomonas vaginalis (TvTIM). We show that the import of the presequence-containing protein into the hydrogenosomal matrix is mediated by the hybrid TIM22-TIM23 complex that includes three highly divergent core components, TvTim22, TvTim23, and TvTim17-like proteins. The hybrid character of the TvTIM is underlined by the presence of both TvTim22 and TvTim17/23, association with small Tim chaperones (Tim9-10), which in mitochondria are known to facilitate the transfer of substrates to the TIM22 complex, and the coupling with TIM23-specific ATP-dependent presequence translocase-associated motor (PAM). Interactome reconstruction based on co-immunoprecipitation (coIP) and mass spectrometry revealed that hybrid TvTIM is formed with the compositional variations of paralogs. Single-particle electron microscopy for the 132-kDa purified TvTIM revealed the presence of a single ring of small Tims complex, while mitochondrial TIM22 complex bears twin small Tims hexamer. TvTIM is currently the only TIM visualized outside of Opisthokonta, which raised the question of which form is prevailing across eukaryotes. The tight association of the hybrid TvTIM with ADP/ATP carriers (AAC) suggests that AAC may directly supply ATP for the protein import since ATP synthesis is limited in hydrogenosomes.
CONCLUSIONS: The hybrid TvTIM in hydrogenosomes represents an original structural solution that evolved for protein import when Δψ is negligible and remarkable example of evolutionary adaptation to an anaerobic lifestyle.

Keywords: Trichomonas vaginalis ; Hydrogenosomes; Mitochondria; Parasite; Presequence translocase-associated motor; Protein import machinery; TIM22 complex; TIM23 complex

DOI: https://doi.org/10.1186/s12915-024-01928-8

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