bims-tofagi 2025-03-30 papers

Issue of 2025–03–30
four papers selected by
Michele Frison, University of Cambridge

Biol Chem. 2025 Mar 28.

Unclogging of the TOM complex under import stress.

Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor proteins on cytosolic ribosomes. Mitochondrial protein translocases sort the precursor proteins into the mitochondrial sub-compartments: outer and inner membrane, the intermembrane space and the matrix. The translocase of the outer mitochondrial membrane (TOM complex) constitutes the major import site for most of these precursor proteins. Defective protein translocases, premature folding of the precursor, or depletion of the membrane potential can cause clogging of the TOM channel by a precursor protein. This clogging impairs further protein import and leads to accumulation of precursor proteins in the cell that perturbates protein homeostasis, leading to proteotoxic stress in the cell. Therefore, unclogging of the translocon is critical for maintaining mitochondrial and cellular function. Ubiquitylation and AAA-ATPases play a central role in the extraction of the precursor proteins to deliver them to the proteasome for degradation. Here we summarize our understanding of the molecular mechanisms that remove such translocation-stalled precursor proteins from the translocation channel to regenerate the TOM complex for protein import.

Keywords: AAA ATPases; TOM complex; mitochondria; protein import; quality control; ubiquitylation

DOI: https://doi.org/10.1515/hsz-2025-0110

Biomolecules. 2025 Mar 18. pii: 433. [Epub ahead of print]15(3):

The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.

Paola Zanfardino, Alessandro Amati, Mirko Perrone, Vittoria Petruzzella.

Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.

Keywords: autophagy; mTOR signaling; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases; oxidative phosphorylation; proliferation; senescence

DOI: https://doi.org/10.3390/biom15030433

Neuroscience. 2025 Mar 24. pii: S0306-4522(25)00254-4. [Epub ahead of print]

Defective PINK1-dependent mitophagy is involved in high glucose-induced neurotoxicity.

Yongsheng Bian, Yimei Yang, Jun Chen, Jian Liu, Yan Tao, Zhongjie Liu, Lijin Huang.

Neuropathic pain often complicates diabetes progression, yet the pathogenic mechanisms are poorly understood. Defective mitophagy is linked to various diabetic complications like nephropathy, cardiomyopathy, and retinopathy. To investigate the molecular basis of hyperglycemia-induced painful diabetic neuropathy (PDN), we examined the effect of high glucose on the PTEN-induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin)-mediated mitophagy pathway in ND7/23 cells. Cells were treated with different glucose concentrations (25, 50, 75 mM) for various durations (24, 48, 72 h). Additionally, cells were exposed to high glucose (50 mM) with or without 100 nM rapamycin (a mitophagy enhancer) for 48 h, or transfected with PINK1 siRNA. We assessed protein levels of mitophagy-related genes (PINK1, Parkin, P62, LC3B) and apoptotic markers (cleaved-Caspase3) via Western blotting. High glucose significantly reduced the expression of autophagy-related proteins PINK1 and Parkin in a time- and concentration-dependent manner compared to controls. Rapamycin counteracted the inhibitory effects of high glucose on PINK1/Parkin-mediated mitophagy, while PINK1 siRNA transfection showed similar outcomes, confirming the inhibitory impact of high glucose on mitophagy. Moreover, high glucose induced apoptosis by suppressing PINK1/Parkin-mediated mitophagy, causing cytotoxic effects in ND7/23 cells which is derived from the fusion of mouse neuroblastoma cells and rat dorsal root ganglion (DRG) cells. Our findings suggest that hyperglycemia-induced disruption of the PINK1/Parkin mitophagy pathway impairs mitochondrial homeostasis, leading to apoptosis. Therefore, targeting PINK1 pathway activation or restoring mitophagy might be a promising therapeutic strategy for PDN treatment.

Keywords: Apoptosis; Diabetic; Mitophagy; Neurotoxicity; PDN; PINK1; Rapamycin

DOI: https://doi.org/10.1016/j.neuroscience.2025.03.052

Autophagy. 2025 Mar 22.

TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.

Jiong Yan, Xin Chen, Swati Choksi, Zheng-Gang Liu.

Selective clearance of damaged mitochondria through mitophagy is crucial for the maintenance of mitochondrial homeostasis. While mitophagy can be activated by various mitochondrial toxins, the physiologically relevant signal that triggers mitophagy is less studied. TGFB/TGFβ signaling has been linked to autophagic induction, but its specific role in mitophagy is not well understood. Here, we discovered a novel mitophagy induction paradigm stimulated by TGFB1. The mitophagic response is exclusively mediated by SMAD2, SMAD3, and SMAD4 underlying the TGFB receptor signaling. The transcriptional regulation activates genes involved in the canonical autophagic pathway which is required for the TGFB1-induced mitophagy. Moreover, TGFB1 signaling promotes mitophagic flux by upregulating PLSCR3 that externalizes cardiolipin in conjunction with the MAP1LC3/LC3/GABARAPs-interacting receptor proteins (BNIP3L/NIX, BNIP3, and FUNDC1)-dependent mechanism. Overall, our study characterized the essential components engaged in the TGFB1-induced mitophagy and demonstrated that TGFB is an important signal that induces mitophagy.

Keywords: ATG8; BNIP3; BNIP3L/NIX; PLSCR3; TGFB/TGFβ; mitophagy

DOI: https://doi.org/10.1080/15548627.2025.2483441