bims-mitpro 2025-04-06 papers

Issue of 2025–04–06
two papers selected by
Andreas Kohler, Umeå University

Trends Biochem Sci. 2025 Mar 27. pii: S0968-0004(25)00050-7. [Epub ahead of print]

Understanding mitochondrial protein import: a revised model of the presequence translocase.

Naintara Jain, Agnieszka Chacinska, Peter Rehling.

Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs precursor proteins across the outer mitochondrial membrane (OMM) via the Translocase of the Outer Membrane (TOM) complex and into the matrix or inner mitochondrial membrane (IMM) via the Translocase of the Inner Membrane 23 (TIM23) complex. While classical biochemical studies provided detailed mechanistic insights into the composition and mechanism of the TIM23 complex, recent cryogenic-electron microscopy (cryo-EM) data challenge these established models and propose a revised model of translocation in which the TIM17 subunit acts as a 'slide' for precursor proteins, with Tim23 acting as a structural element. In this review, we summarize existing models, highlighting the questions and data needed to reconcile these perspectives, and enhance our understanding of TIM23 complex function.

Keywords: inner mitochondrial membrane (IMM); mitochondria; presequence pathway; protein sorting; protein translocation; translocase of the inner membrane 23 (TIM23)

DOI: https://doi.org/10.1016/j.tibs.2025.03.001

Sci Adv. 2025 Apr 04. 11(14): eadr6415

Retromer promotes the lysosomal turnover of mtDNA.

Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.

Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.

DOI: https://doi.org/10.1126/sciadv.adr6415