bims-mitpro 2026-04-12 papers

Issue of 2026–04–12
two papers selected by
Andreas Kohler, Umeå University

Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6

Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2526136123

mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.

Rupa Banerjee, Vanessa Trauschke, Nils Bertram, Ina Aretz, Christof Osman, Don C Lamb, Dejana Mokranjac.

Heat shock proteins 70 (Hsp70) represent a ubiquitous and conserved family of molecular chaperones involved in a variety of cellular processes. The conformational cycles of several Hsp70 chaperones, driven by ATP binding and hydrolysis, and regulated by cochaperones and substrate proteins, were analyzed in vitro in great detail. In contrast, little is known about the conformation Hsp70s adopt in their natural environments. In mitochondria, mtHsp70 is distributed between the TIM23 complex at the inner membrane, where it is involved in import of proteins from the cytosol, and a matrix-pool that is primarily involved in folding of proteins and prevention of their aggregation. Here, we used fluorescence microscopy to analyze the conformation of mtHsp70 at the single molecule level within physiologically active mitochondria. Our results revealed that the majority of mtHsp70 molecules are present in a substrate-bound state, suggesting that the mtHsp70 network functions at the limits of its capacity. To understand the biological significance of this finding, we modulated the levels of unfolded proteins in the matrix. Unfolded proteins reduced the association of mtHsp70 with the TIM23 complex and specifically impaired mtHsp70-dependent import of proteins. Our data show that unfolded proteins lead to a redistribution of mtHsp70 within mitochondria revealing how mitochondrial proteostasis stress is signaled to the cell-unfolded proteins remove mtHsp70 from the import sites, reducing the efficiency of protein import and initiating cellular programs to rescue or remove dysfunctional mitochondria. Thus, mtHsp70 acts as a mitochondrial quality control sensor that converts proteostasis stress into impaired protein import.

Keywords: Hsp70 chaperones; mitochondria; protein homeostasis; protein import; single molecule FRET

DOI: https://doi.org/10.1073/pnas.2526136123