bims-tofagi 2025-12-28 papers

Issue of 2025–12–28
five papers selected by
Michele Frison, University of Cambridge

Biochem J. 2025 Dec 23. pii: BCJ20253459. [Epub ahead of print]483(1):

Insights into PINK1/Parkin function and dysfunction from Drosophila models.

Seoyoung Park, Nikita Kozhushko, Thomas H Wight, Alexander J Whitworth.

Loss-of-function mutations in PINK1 and PRKN cause familial forms of Parkinson's disease (PD). In vitro studies have revealed incredible insights into the molecular and cell-biological function of these genes, which have focused predominantly on mitophagy - the autophagic degradation of damaged mitochondria. The mechanisms of PINK1/Parkin function ultimately require investigation in an in vivo context using classic genetic approaches in animal models. In this context, Drosophila models have proven to be remarkably informative, in part due to robust phenotypes arising from null mutations. They have revealed important insights into the function of the Pink1 and parkin orthologues, much of which has proven to be conserved in humans. The simplicity, speed and genetic tractability make Drosophila an excellent in vivo model to interrogate the physiological functions of Pink1 and parkin and to rapidly test emerging hypotheses arising from in vitro work. They also represent a powerful model with which to explore the pathological consequences of Pink1/parkin loss in a whole-organism context. In this regard, several themes have emerged from recent studies that likely have significance for the neurodegenerative process in humans, including aberrant activation of immune signalling and consequent inflammation, disruptions to gut integrity and disturbed mitochondrial calcium handling. In this review, we evaluate the current evidence regarding the mechanism(s) of Pink1/parkin-mediated mitochondrial turnover in Drosophila, and discuss the potential implications of recent developments on the consequences of Pink1/parkin mutations and how these may inform the pathogenesis of PD.

Keywords: Drosophila ; PINK1; Parkin; Parkinson’s disease; autophagy; calcium signalling; immune signalling; mitochondria; mitophagy; mtDNA; neurodegeneration

DOI: https://doi.org/10.1042/BCJ20253459

Autophagy. 2025 Dec 26.

Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.

Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.

Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.

Keywords: ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons

DOI: https://doi.org/10.1080/15548627.2025.2610450

Anticancer Drugs. 2025 Dec 24.

Aldehyde dehydrogenase 9A1 promotes cisplatin resistance in laryngeal squamous cell carcinoma by enhancing PTEN-induced kinase 1-Parkin-mediated mitophagy.

Jiawei Gui, Bo Wu, Yutong Fan, Xiaotong Liu, Yuzhe Liu, Haiying Wang, Jun An, Hao Wang, Ruoqing Wu, Liang Li, Jingchun Ge, Hui Xiao.

Cisplatin resistance remains a major challenge in laryngeal squamous cell carcinoma (LSCC) treatment. Aldehyde dehydrogenase 9A1 (ALDH9A1), a mitochondrial matrix protein, is dysregulated in various cancers, but its role in LSCC is unclear. This study demonstrates that ALDH9A1 is significantly downregulated in LSCC tissues, and low ALDH9A1 expression correlates with poor patient prognosis. Functionally, ALDH9A1 overexpression inhibits LSCC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, ALDH9A1 interacts with and stabilizes PTEN-induced kinase 1 (PINK1), leading to activation of PINK1-Parkin-mediated mitophagy. Under cisplatin treatment, ALDH9A1 is upregulated and induces protective mitophagy, contributing to cisplatin resistance. Inhibition of mitophagy with chloroquine sensitizes LSCC cells to cisplatin. These findings identify ALDH9A1 as a key regulator of mitophagy and cisplatin resistance in LSCC, suggesting that targeting the ALDH9A1/PINK1 axis could provide a novel therapeutic strategy for overcoming cisplatin resistance.

Keywords: PTEN-induced kinase 1–Parkin; aldehyde dehydrogenase 9A1; cisplatin resistance; laryngeal squamous cell carcinoma; mitophagy

DOI: https://doi.org/10.1097/CAD.0000000000001799

Biochemistry (Mosc). 2025 Dec;90(12): 1849-1861

Turnover and Quality Control of Mitochondrial DNA.

Wolfram S Kunz.

The quantitative content of mitochondrial DNA (mtDNA) - a multicopy circular genome - is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).

Keywords: determinants of cellular mtDNA content; mtDNA degradation; mtDNA maintenance; mtDNA maintenance disorders; mtDNA replication

DOI: https://doi.org/10.1134/S0006297925602485

Biochemistry (Mosc). 2025 Dec;90(12): 1919-1928

Mechanisms of Intracellular Selection of Mitochondrial DNA.

Georgii Muravyov, Dmitry A Knorre.

Eukaryotic cells contain multiple mitochondrial DNA (mtDNA) molecules. Heteroplasmy is coexistence in the same cell of different mtDNA variants competing for cellular resources required for their replication. Here, we review documented cases of emergence and spread of selfish mtDNA (i.e., mtDNA that has a selective advantage in a cell but decreases cell fitness) in eukaryotic species, from humans to baker's yeast. The review discusses hypothetical mechanisms enabling preferential proliferation of certain mtDNA variants in heteroplasmy. We propose that selfish mtDNAs have significantly influenced the evolution of eukaryotes and may be responsible for the emergence of uniparental inheritance and constraints on the mtDNA copy number in germline cells.

Keywords: heteroplasmy; intracellular selection; mitochondrial DNA; mitophagy; mtDNA quality control; selfish gene

DOI: https://doi.org/10.1134/S0006297925603296