bims-mitpro 2026-08-16 papers

Issue of 2026–08–16
three papers selected by
Andreas Kohler, Umeå University

Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00935-6. [Epub ahead of print]45(8): 117857

Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.

Koyeli Das, Rituparna Samanta, Tamar Ziv, Johannes M Herrmann, Bella Kalderon, Ophry Pines.

Tim23 is an essential component of the mitochondrial inner membrane translocase and Sfc1 is a carrier that exchanges succinate for fumarate across that membrane. Sfc1 and succinic acid availability regulate dual targeting of fumarase and aconitase by facilitating mitochondrial import of their newly synthesized precursors, as shown by pulse-chase experiments. Here, we show that Sfc1 associates with Tim23 in vivo, and succinate modulates this association, which in turn affects mitochondrial protein import. Physical interaction between Tim23 and Sfc1 was proven by co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) and biotin-based proximity labeling (TurboID). Proximity labeling and structural modeling-informed mutagenesis allowed us to dissect the carrier activity of Sfc1 from its function as a TIM23 regulator. We performed Rosetta-MP docking of Sfc1 and Tim23 to envisage the interface. Thus, our findings show that metabolites can regulate mitochondrial import and adjust the segregation of key metabolic enzymes between the cytosol and mitochondria.

Keywords: CP: cell biology; CP: metabolism; Tim23; aconitase; dual targeting; fumarase; glyoxylate shunt; metabolic signaling; metabolites; mitochondrial protein import; succinate-fumarate carrier; tricarboxylic acid cycle

DOI: https://doi.org/10.1016/j.celrep.2026.117857

Burns Trauma. 2026 ;14 tkag037

Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.

Yanmin Xin, Yiting He, Xingguo Liu.

The mitochondrial unfolded protein response (UPRmt) is a conserved mitochondrial stress response that is activated by mitochondrial dysfunction to maintain proteostasis. Although UPRmt has been extensively studied in aging and cancer, its role in trauma and critical illness remains poorly understood. Here, we propose a unifying conceptual framework in which UPRmt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPRmt activation triggered by diverse insults and highlight how UPRmt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPRmt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPRmt in trauma and critical illness. Moderate activation promotes mitochondrial recovery, limits reactive oxygen species accumulation, and supports immune cell function, thereby enhancing tissue resilience and repair. In contrast, sustained or dysregulated UPRmt contributes to mitochondrial failure, sterile inflammation, and the progression to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Furthermore, we discuss emerging evidence linking UPRmt to immune regulation and inflammatory responses, and propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for a broad spectrum of human diseases. Crucially, we synthesize how UPRmt mechanisms contribute to post-traumatic mitochondrial damage, sterile inflammation, SIRS, and MODS. We propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for trauma, burns, and critical illness.

Keywords: Immunity; MODS; SIRS; Trauma; UPRmtproteostasis

DOI: https://doi.org/10.1093/burnst/tkag037

Sci Adv. 2026 Aug 14. 12(33): eaeh0657

Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.

Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li.

Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.

DOI: https://doi.org/10.1126/sciadv.aeh0657