bims-tofagi 2025-07-13 papers

Issue of 2025–07–13
five papers selected by
Michele Frison, University of Cambridge

Autophagy. 2025 Jul 07.

Activation of endogenous PRKN by structural derepression is linked to increased turnover of the E3 ubiquitin ligase.

Loss-of-function mutations in the PINK1 and PRKN genes are the most common cause of early-onset Parkinson disease (PD). The encoded enzymatic pair selectively identifies, labels, and targets damaged mitochondria for degradation via the macroautophagy/autophagy-lysosome system (mitophagy). This pathway is cytoprotective and efforts to activate mitophagy are pursued as therapeutic avenues to combat PD and other neurodegenerative disorders. When mitochondria are damaged, the ubiquitin kinase PINK1 accumulates and recruits PRKN from the cytosol to activate the E3 ubiquitin ligase from its auto-inhibited conformation. We have previously designed several mutations that effectively derepress the structure of PRKN and activate its enzymatic functions in vitro. However, it remained unclear how these PRKN-activating mutations would perform endogenously in cultured neurons or in vivo in the brain. Here, we gene-edited neural progenitor cells and induced pluripotent stem cells to express PRKN-activating mutations in dopaminergic cultures. All tested PRKN-activating mutations indeed enhanced the enzymatic activity of PRKN in the absence of exogenous stress, but their hyperactivity was linked to their own PINK1-dependent degradation. Strikingly, in vivo in a mouse model expressing an equivalent activating mutation, we find the same relationship between PRKN enzymatic activity and protein stability. We conclude that PRKN degradation is the consequence of its structural derepression and enzymatic activation, thus resulting only in a temporary gain of activity. Our findings imply that pharmacological activation of endogenous PRKN will lead to increased turnover and suggest that additional considerations might be necessary to achieve sustained E3 ubiquitin ligase activity for disease treatment.

Keywords: Autophagy; PINK1; Parkin; mitophagy; parkinson’s disease

DOI: https://doi.org/10.1080/15548627.2025.2531025

FASEB Bioadv. 2025 Jul;7(7): e70030

PINK1 Loss of Function Selectively Alters the Mitochondrial-Derived Vesicle Pathway.

Charlotte L Collier, Colleen Ruedi, Naomi J Thorne, David A Tumbarello.

Cell homeostasis and metabolic control require the efficient function of mitochondria and implementation of quality control pathways following damage. Cells have various discrete pathways of mitochondrial quality control (mitoQC) to maintain the healthy network. PINK1 and Parkin are two key players in mitoQC, most highly associated with the ubiquitin-dependent capture and degradation of whole mitochondria by autophagy. However, these proteins have alternative roles in repair routes directing locally damaged cargo to the lysosome, such as the mitochondrial-derived vesicle (MDV) pathway. We aimed to clarify the role of PINK1 and determine how its loss of function impacts mitochondrial dynamics and quality control. Results indicate PINK1 knockout (KO) has little impact on whole mitochondrial turnover in response to damage in SH-SY5Y cells, whereas both PINK1 and Parkin KO cells have healthy mitochondrial networks with efficient ATP production. However, TOM20 positive outer-membrane and damage-induced PDH-positive inner-membrane MDVs are elevated in PINK1 KO cells. Although, in contrast to Parkin KO, this is not due to a defect in trafficking to a LAMP1-positive compartment and may instead indicate increased damage-induced flux. In comparison, loss of Atg5-dependent mitophagy has no effect on whole mitochondrial turnover and only results in a limited elevation in inner-membrane MDVs in response to damage, indicating autophagy-independent mechanisms of whole mitochondrial turnover and a minor compensatory increase in damage-induced MDVs. Therefore, these data suggest PINK1 and Parkin are dispensable for whole mitochondrial turnover, but following their perturbation have disparate effects on the MDV pathway.

Keywords: Parkinson's; lysosome; membrane trafficking; mitochondria; mitochondrial quality control; vesicle transport

DOI: https://doi.org/10.1096/fba.2024-00200

Neurobiol Dis. 2025 Jul 04. pii: S0969-9961(25)00235-9. [Epub ahead of print]213 107019

Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.

Li Zhang, Alireza Pouya, Janina Kopetzky, Sara Bitar, Christina Wolf, Federica Dal Bello, David Gomez-Zepeda, Stefan Tenzer, Axel Methner.

Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.

Keywords: BNIP3; Charcot-Marie-tooth (CMT) disease; Drosophila; GDAP1; Mitophagy

DOI: https://doi.org/10.1016/j.nbd.2025.107019

Redox Biol. 2025 Jul 03. pii: S2213-2317(25)00264-2. [Epub ahead of print]85 103751

Targeting Dio3 to enhance mitophagy and ameliorate skeletal muscle wasting in sepsis.

Gang Wang, Ming Chen, Yuheng Zhang, Dacheng Wang, Tao Gao, Jianfeng Duan, Huimin Lu, Minhua Cheng, Yun Xu, Xiaoyao Li, Yan Wang, Ke Cao, Wenkui Yu.

Recent studies highlight the role of skeletal muscle wasting in the sepsis-associated long-term mortality. Despite clinical recommendations for increased protein intake to counteract muscle wasting, the outcomes have been suboptimal, suggesting that anabolic resistance should be considered in addition to nutritional support. Emerging evidence suggests that impaired mitophagy hampers anabolic processes in skeletal muscle, exacerbating muscle wasting in sepsis. Furthermore, thyroid hormone (TH), which is essential for both anabolism and mitophagy, is locally inactivated by type 3 Deiodinase (Dio3) at the onset of sepsis, potentially disrupting mitophagy and contributing to anabolic resistance. Here we demonstrate that local hypothyroidism is a key factor impairing mitophagy in skeletal muscle during early sepsis, leading to metabolic disturbances and muscle wasting. Dio3 knockdown preserves muscle mass, and ameliorates metabolic dysfunction via mitophagy promotion in sepsis models. Mechanistically, the knockdown of Dio3 triggers an upregulation of NRK2, facilitating the restoration of NAD salvage synthesis. This enhancement of NAD levels subsequently activates Sirtuins deacetylase, which in turn decreases PINK1 acetylation, preventing its proteolytic processing by OMA1. Therefore, targeting Dio3 offers a promising therapeutic approach to counteract sepsis-induced muscle wasting.

DOI: https://doi.org/10.1016/j.redox.2025.103751

Sci Signal. 2025 Jul 08. 18(894): eaea2255

Mutant α-synuclein takes down autophagy.

Leslie K Ferrarelli.

Parkinson's disease-associated α-synuclein impairs autophagy by hijacking the cell's acetylation machinery.

DOI: https://doi.org/10.1126/scisignal.aea2255