bims-smemid 2026-06-07 papers

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

bioRxiv. 2026 May 21. pii: 2026.05.18.726122. [Epub ahead of print]

Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.

David Sokolov, Eric Zheng, Serwah Danquah, Madeleine L Hart, Lucas B Sullivan.

Succinate dehydrogenase (SDH) supports cancer cell proliferation by enabling oxidative biosynthesis of the amino acid aspartate, yet SDH loss can also drive tumorigenesis. To cope with SDH loss, cancer cells can engage alternative aspartate synthesis pathways; however, the variables dictating pathway usage and adaptive mechanisms involved are incompletely understood. Here, we systematically profile the adaptation of SDH-knockout cancer cells and find that cells can adapt to SDH loss via at least two distinct mechanisms: suppression of respiratory complex I or upregulation of pyruvate carboxylase. Each route gives rise to distinct metabolic states with both shared and unique dependencies, but either route allows cells to overcome aspartate limitation, improve proliferative fitness, and mitigate pyrimidine-dependent replication stress. Overall, this work provides a comprehensive view of adaptive aspartate synthesis in SDH-deficient cancer cells, highlights a remarkable redox-constrained metabolic plasticity, and nominates potential metabolic vulnerabilities likely to be shared among SDH-deficient cancer cells.

DOI: https://doi.org/10.64898/2026.05.18.726122

bioRxiv. 2026 May 22. pii: 2026.05.20.726656. [Epub ahead of print]

Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.

Santanu Ghosh, Andrew F Jarvis, Jordi C J Hintzen, Nate R McKnight, Pedro Costa-Pinheiro, Noelle H Noughton, Yumi Kim, Alison Jaccard, Scot C Leary, Paul A Cobine, Caroline R Bartman, Gina M DeNicola, Nathaniel W Snyder, Kathryn E Wellen, George M Burslem, Donita C Brady.

Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.

DOI: https://doi.org/10.64898/2026.05.20.726656

Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00184-1. [Epub ahead of print]38(6): 1089-1092

Functional specialization within the mitochondrial network: Are all mitochondria created equal?

Jessica B Spinelli.

Mitochondria are classically viewed as a uniform ATP-producing network; however, a growing body of evidence suggests distinct subpopulations exist within tissues and even single cells. Here, I highlight evidence supporting the presence of functionally distinct mitochondria and propose mechanisms by which these subpopulations are formed and regulated.

DOI: https://doi.org/10.1016/j.cmet.2026.04.019