bims-mitpro 2026-02-15 papers

Issue of 2026–02–15
four papers selected by
Andreas Kohler, Umeå University

Protein Sci. 2026 Mar;35(3): e70491

Mitochondrial presequences are more than just address labels.

Erik Marcel Heller, Svenja Lenhard, Doron Rapaport, Johannes Herrmann.

Most mitochondrial proteins are synthesized in the cytosol as precursor proteins with N-terminal presequences. These presequences serve as targeting signals that facilitate the binding to mitochondrial surface receptors and translocation across the mitochondrial membranes. However, recent studies showed that presequences can be more than address tags. They can contain degradation signals recognized by components of the ubiquitin-proteasome system, and therefore, serve as timers that determine the lifespan of newly synthesized precursor proteins. Moreover, presequences can interact with components of the cytosolic chaperone system to prevent or delay precursor folding. Finally, presequences of some dually localized proteins contain targeting information not only for mitochondria but also for other cellular destinations such as the nuclear lumen or chloroplasts in plant cells. Thus, presequences contain multifaceted information to endow mitochondrial precursor proteins with specific properties that are critical for the early steps of mitochondrial protein biogenesis.

Keywords: Presequence; chaperones; mitochondria; proteasome; protein import; ubiquitin ligases

DOI: https://doi.org/10.1002/pro.70491

Protein Sci. 2026 Mar;35(3): e70493

In and out of the mitochondrial intermembrane space.

Fara van der Schans, Kostas Tokatlidis, Daniela G Vitali.

Mitochondria are essential organelles constituted by two membranes, the outer (OMM) and inner mitochondrial membrane (IMM), and two aqueous compartments, the intermembrane space (IMS) and the matrix. Although mitochondria contain their own genome, which encodes for 13 proteins in humans (8 in budding yeast), the vast majority (99%) of mitochondrial proteins are encoded by the nuclear DNA and imported into the organelle co- or post-translationally. The IMS lies between the cytosol and the matrix, making it a strategic hub for monitoring the mitochondrial proteome. All IMS-resident proteins are nuclear-encoded and play critical roles in cellular pathways, such as redox regulation, calcium signaling, apoptosis, and hypoxia response. Furthermore, most mitochondrial proteins pass through the IMS en route to their final destination within the organelle. During this transit, their targeting and folding states are carefully monitored: properly folded proteins are retained, while misfolded or potentially toxic polypeptides are retrotranslocated and degraded. In this review, we highlight the mechanisms by which proteins are sorted into the IMS and discuss its central role in regulating mitochondrial proteostasis and maintaining mitochondrial function.

Keywords: Mia40; intermembrane space; oxidative folding; proteostasis

DOI: https://doi.org/10.1002/pro.70493

Nat Rev Mol Cell Biol. 2026 Feb 13.

Mechanisms and disease relevance of mitochondrial translation in humans.

Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.

Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.

DOI: https://doi.org/10.1038/s41580-026-00948-2

J Biol Chem. 2026 Feb 06. pii: S0021-9258(26)00134-1. [Epub ahead of print] 111264

Molecular mechanisms of mitochondrial AAA+ proteases.

S Quinn W Currie, Monica M Goncalves, Aaron D Schimmer, Siavash Vahidi.

Mitochondrial AAA+ proteases, LONP1, ClpXP, YME1L (i-AAA), and the m-AAA complex, maintain protein quality and shape organelle function. Growing interest in these enzymes stems from their association with neurodegeneration, cardiomyopathy, metabolic disease, and cancer. Recent structural and biophysical work clarifies how ATP-driven conformational cycles enable substrate recognition, unfolding, translocation, and proteolysis, and how assembly state, subunit composition, and regulatory inputs tune activity. These insights help interpret patient variants and guide experiments that connect mechanism to phenotype. Here we review shared mechanistic principles across the four proteases, contrast their architectures and regulatory features, and relate these properties to substrate selection and disease mechanisms, with emphasis on evidence from structural, biochemical, and cellular studies. We also survey strategies to modulate function. Small molecules, exemplified by Dordaviprone (ONC201) which activate human ClpP, provide proof of concept, and emerging modalities such as engineered macromolecules, may offer the selectivity and localization required to correct disease mechanisms or exploit disease dependencies. By integrating mechanism, disease links, and modulation strategies, this review provides a framework for translating basic insight on mitochondrial AAA+ proteases into new tools and, ultimately, therapies.

Keywords: ClpXP; LONP1; YME1L; i-AAA; m-AAA; mitochondrial proteostasis

DOI: https://doi.org/10.1016/j.jbc.2026.111264