bims-mitpro Biomed News
on Mitochondrial proteostasis
Issue of 2025–05–18
four papers selected by
Andreas Kohler, Umeå University



  1. J Cell Sci. 2025 May 01. pii: jcs263757. [Epub ahead of print]138(9):
      Mitochondria are metabolic hubs that are essential for cellular homeostasis. Most mitochondrial proteins are translated in the cytosol and imported into the organelle. However, import machineries can become overwhelmed or disrupted by physiological demands, mitochondrial damage or diseases, such as metabolic and neurodegenerative disorders. Impaired import affects mitochondrial function and causes un-imported pre-proteins to accumulate not only in the cytosol but also in other compartments, including the endoplasmic reticulum and nucleus. Quality control pathways have evolved to mitigate the accumulation of these mistargeted proteins and prevent proteotoxicity. In this Cell Science at a Glance article and the accompanying poster, we summarize the fate of un-imported mitochondrial proteins and the compartment-specific quality control pathways that regulate them.
    Keywords:  Mitochondrial protein import; Mitochondrial stress; Protein quality control
    DOI:  https://doi.org/10.1242/jcs.263757
  2. J Cell Biol. 2025 Jul 07. pii: e202408166. [Epub ahead of print]224(7):
      BNIP3 and NIX are the main receptors for mitophagy, but their mechanisms of action remain elusive. Here, we used correlative light EM (CLEM) and electron tomography to reveal the tight attachment of isolation membranes (IMs) to mitochondrial protrusions, often connected with ER via thin tubular and/or linear structures. In BNIP3/NIX-double knockout (DKO) HeLa cells, the ULK1 complex and nascent IM formed on mitochondria, but the IM did not expand. Artificial tethering of LC3B to mitochondria induced mitophagy that was equally efficient in DKO cells and WT cells. BNIP3 and NIX accumulated at the segregated mitochondrial protrusions via binding with LC3 through their LIR motifs but did not require dimer formation. Finally, the average distance between the IM and the mitochondrial surface in receptor-mediated mitophagy was significantly smaller than that in ubiquitin-mediated mitophagy. Collectively, these results indicate that BNIP3 and NIX are required for the tight attachment and expansion of the IM along the mitochondrial surface during mitophagy.
    DOI:  https://doi.org/10.1083/jcb.202408166
  3. Nat Rev Mol Cell Biol. 2025 May 14.
      Mitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F1Fo-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein-lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions.
    DOI:  https://doi.org/10.1038/s41580-025-00854-z
  4. J Cell Sci. 2025 May 15. pii: jcs.263850. [Epub ahead of print]
      Mitochondria are dynamic organelles exhibiting diverse shapes. While the variation of shapes, ranging from spheres to elongated tubules, and the transition between them, are clearly seen in many cell types, the molecular mechanisms governing this morphological variability remain poorly understood. Here, we propose a biophysical model for the shape transition between spheres and tubules based on the interplay between the inner and outer mitochondrial membranes. Our model suggests that the difference in surface area, arising from the folding of the inner membrane into cristae, correlates with mitochondrial elongation. Analysis of live cell super-resolution microscopy data supports this correlation, linking elongated shapes to the extent of cristae in the inner membrane. Knocking down cristae shaping proteins further confirms the impact on mitochondrial shape, demonstrating that defects in cristae formation correlate with mitochondrial sphericity. Our results suggest that the dynamics of the inner mitochondrial membrane are important not only for simply creating surface area required for respiratory capacity, but go beyond that to affect the whole organelle morphology. This work explores the biophysical foundations of individual mitochondrial shape, suggesting potential links between mitochondrial structure and function. This should be of profound significance, particularly in the context of disrupted cristae shaping proteins and their implications in mitochondrial diseases.
    Keywords:  Biophysical model; Cristae; Membrane remodeling; Mitochondrial membranes; Mitochondrial shape; Organelle shape
    DOI:  https://doi.org/10.1242/jcs.263850