bims-mitpro 2026-04-26 papers

Issue of 2026–04–26
three papers selected by
Andreas Kohler, Umeå University

Protein Sci. 2026 May;35(5): e70553

Proteolytic control of mitochondrial protein translocases.

Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.

Keywords: mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control

DOI: https://doi.org/10.1002/pro.70553

Protein Sci. 2026 May;35(5): e70587

Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.

Shunsuke Matsumoto, Suzuka Ono, Toshiya Endo.

Mitochondria are enclosed by a double-membrane structure composed of the outer and inner membranes, and this architectural organization underlies their diverse cellular functions. In particular, the mitochondrial outer membrane serves as an essential interface between the cytosol and the mitochondrial interior, regulating the flux of proteins, lipids, small molecules, and ions through the coordinated activities of its resident proteome. Consequently, structural and functional defects of outer membrane proteins are subject to continuous surveillance, and aberrant proteins are rapidly recognized and degraded. Defects in precursor translocation or translation can lead to the stalling of precursor proteins at the primary protein import gate, the TOM complex. Such situations are resolved by multiple quality control systems operating across both the mitochondria and the cytosol. In addition, proteins normally destined for the endoplasmic reticulum or peroxisomes may be mistargeted to mitochondria, and these mislocalized proteins are likewise managed through dedicated mechanisms that promote their degradation or re-targeting. In this review, we summarize current insights into the molecular factors and mechanisms that maintain proteostasis at the mitochondrial outer membrane.

Keywords: mitochondria; outer membrane; protein degradation; quality control; re‐targeting

DOI: https://doi.org/10.1002/pro.70587

Exp Neurol. 2026 Apr 16. pii: S0014-4886(26)00151-2. [Epub ahead of print]402 115787

mtHsp70 overexpression enhances neuroprotection through ATF5-dependent UPRmt signaling after traumatic brain injury.

Yuanqing Zhang, Yi Jin, Runze Han, Yucheng Shen, Zongqi Wang, Xiaoou Sun, Jiangang Liu.

Traumatic brain injury (TBI) induces secondary neuronal damage, in which mitochondrial dysfunction plays a central role. Mitochondrial heat shock protein 70 (mtHsp70) is a key mitochondrial chaperone involved in protein folding and proteostasis, yet its role in TBI pathology remains unclear. In the present study, we investigated the neuroprotective function of mtHsp70 and its underlying mechanisms using a controlled cortical impact (CCI) mouse model. We found that CCI selectively reduced mtHsp70 levels within mitochondria, accompanied by its cytoplasmic accumulation, while total cellular mtHsp70 expression remained unchanged. Stereotactic AAV-mediated overexpression of mtHsp70 in the cortex significantly reduced neuronal apoptosis, improved motor and cognitive behavioral outcomes, and increased neuronal survival following CCI. In vitro, mtHsp70 overexpression in HT22 cells attenuated H₂O₂-induced neuronal injury, improved mitochondrial respiration (OCR), and reduced mitochondrial protein aggregation. Mechanistically, mtHsp70 overexpression increased the expression of mitochondrial unfolded protein response (UPRmt)-related proteins, including HSP60 and Lonp1, and restored mitochondrial membrane potential. Importantly, ATF5 knockdown attenuated mtHsp70-induced upregulation of UPRmt-associated proteins and diminished mitochondrial respiratory improvement, suggesting that mtHsp70-mediated protection is dependent on ATF5-associated UPRmt signaling. Together, these findings indicate that mitochondrial mtHsp70 deficiency contributes to neuronal injury after CCI, whereas restoration of mtHsp70 improves mitochondrial proteostasis and neuronal survival. Targeting the mtHsp70-UPRmt pathway may represent a potential therapeutic strategy for TBI.

Keywords: DNAJA3; Mitochondrial proteostasis; Mitochondrial unfolded protein response; Neuroprotection; Traumatic brain injury; mtHsp70

DOI: https://doi.org/10.1016/j.expneurol.2026.115787