bims-mitpro 2026-06-07 papers

Issue of 2026–06–07
five papers selected by
Andreas Kohler, Umeå University

Protein Sci. 2026 Jul;35(7): e70662

Regulation of mitochondrial protein translocases.

Mitochondria are essential for cellular health, and their function is underlain by the plasticity of the mitochondrial proteome. Most mitochondrial proteins are nuclear encoded, synthesized in the cytosol, and require precise import into mitochondrial subcompartments to fulfill their proper functions. Multimeric mitochondrial translocases ensure accurate protein localization and membrane integration. Recent work has begun to reveal how translocase activity and composition are dynamically regulated within mammalian cells. This review discusses regulatory mechanisms, including phosphorylation and protein degradation, that emerge as important players in adjusting the capacity and/or selectivity of the mitochondrial translocase to metabolic demands. Particular emphasis will be placed on the TIM23 complex as an emerging regulator of the inner membrane and matrix proteome composition.

Keywords: TIM23 complex; TOM complex; mitochondria; mitochondrial biogenesis; proteases; protein translocases; protein turnover

DOI: https://doi.org/10.1002/pro.70662

Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546

Consequences of defective mitochondrial protein import: From targeting signals to pathology.

Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.

Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.

Keywords: Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex

DOI: https://doi.org/10.1016/j.bbamem.2026.184546

Protein Sci. 2026 Jul;35(7): e70665

Redox signals and oxidative stress in the control of mitochondrial protein import.

Lidwina Hasberg, Viktoria Katharina Lauterbach, Torsten Ochsenreiter, Jan Riemer.

Mitochondrial protein import is essential for organelle biogenesis and cellular homeostasis. It operates in an environment that is intrinsically shaped by redox chemistry. Mitochondria are major sources of reactive oxygen species (ROS), which arise as by-products of oxidative phosphorylation. Cells therefore maintain sophisticated ROS-handling systems, including compartmentalized antioxidant networks, to balance redox signaling with protection from oxidative stress. Increasing evidence indicates that these redox conditions directly influence mitochondrial protein import at multiple levels. In this review, we provide an overview of ROS production, ROS signaling, and oxidative stress in relation to mitochondrial protein import. We outline the major mitochondrial protein import pathways, and discuss how their activity is modulated by redox-dependent mechanisms. A particular focus is placed on the mitochondrial disulfide relay system of the intermembrane space, which directly couples protein import to redox chemistry through oxidative folding, and how it is influenced by the local redox environment. Collectively, we propose that mitochondrial protein import is partially governed by redox-dependent mechanisms, enabling integration of metabolic state, stress responses, and signaling pathways.

Keywords: disulfide relay; mitochondrial protein import; oxidative stress; reactive oxygen species (ROS); redox signaling

DOI: https://doi.org/10.1002/pro.70665

Nat Commun. 2026 May 30.

Fmp30p is a mitochondrial phosphatidylinositol hydrolase that modulates CoQ biosynthesis.

Zakery N Baker, Rachel M Guerra, Sean W Rogers, David J Pagliarini.

Organellar membranes feature bespoke lipid compositions; however, the enzymes that craft these compositions and the functional implications these lipids exert on membrane protein organization and activity are insufficiently understood. Here, we discover that the inner mitochondrial membrane protein Fmp30p, a member of the metallo-β-lactamase superfamily, displays phospholipase type D activity toward phosphatidylinositol (PI)-a notable mitochondrial membrane component with unclear functional roles. FMP30 deletion caused substantial and specific elevation of PI species in purified mitochondria. Augmenting mitochondrial PI levels in this way, or by targeting established PI-modifying enzymes to the organelle, increased coenzyme Q (CoQ) biosynthesis concomitant with elevated expression of CoQ-related enzymes and enhanced CoQ metabolon formation. Collectively, our work establishes Fmp30p as a mitochondrial PI phospholipase related to CoQ biology and reveals the broader importance of inner membrane PI in regulating mitochondrial function.

DOI: https://doi.org/10.1038/s41467-026-73766-x

J Biol Chem. 2026 Jun 04. pii: S0021-9258(26)02107-1. [Epub ahead of print] 113235

Ago1 is required for the regulation of mitochondrial translation under heat stress in S. pombe.

Mengling Yu, Yuanqi Xu, Yijing Lu, Minjie Li, Yucheng Yao, Gang Feng, Ying Huang, Jinjie Shang.

Mitochondrial protein synthesis is a critical component of OXPHOS complexes, vital for both mammals and Schizosaccharomyces pombe. In our study, we investigated the effect of heat stress on mitochondria, analyzed the mitochondrial proteome and found that during heat stress, the translation of all mtDNA-encoded transcripts was impaired, leading to a reduction in the steady-state levels of mtDNA-encoded proteins, suggesting that heat stress plays a general role in mitochondrial protein synthesis. We also found that heat stress affects the association of mitochondrial translation initiation factors to mitoribosomal small subunits. Interestingly, ago1 deletion compensates for the heat-induced disruption of the interaction between mitochondrial translation initiation factor and mitoribosomes, leading to partial recovery of both translation and steady-state levels of mtDNA-encoded proteins in S. pombe. Under heat stress, Ago1 accumulates in the mitochondrial matrix. C-terminal truncation ablates this localization and abolishes rescue of translational suppression, confirming mitochondrial targeting is essential for regulatory function. Furthermore, our data demonstrate that Ago1's small RNA-loading related N-terminal domain is required for heat-induced translational suppression and that Ago1 physically engages with mitochondrial RNAs, collectively indicating potential RNA interference (RNAi) activity within mitochondria. These findings provide insight into the regulation of mitochondrial protein synthesis in heat stress.

Keywords: Heat stress; Mitochondria; Mitochondrial protein synthesis; Mitochondrial translation; Schizosaccharomyces pombe

DOI: https://doi.org/10.1016/j.jbc.2026.113235