bims-tofagi 2025-02-02 papers

Issue of 2025–02–02
four papers selected by
Michele Frison, University of Cambridge

Life Metab. 2025 Feb;4(1): loae040

Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.

Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.

Keywords: G6PD; NADPH; PINK1; PPP; ROS; mitophagy

DOI: https://doi.org/10.1093/lifemeta/loae040

Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2412029122

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

Keywords: LRRK2; PINK1; brain; ciliogenesis; phosphorylation

DOI: https://doi.org/10.1073/pnas.2412029122

Cell Death Dis. 2025 Jan 28. 16(1): 52

The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance.

Maria Josè Sisalli, Elena D'Apolito, Ornella Cuomo, Giovanna Lombardi, Michele Tufano, Lucio Annunziato, Antonella Scorziello.

Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance to lethal cerebral ischemia. It has been demonstrated that hypoxia-induced Seven in absentia Homolog 2 (Siah2) E3-ligase activation influences mitochondrial dynamics promoting the degradation of mitochondrial proteins. Therefore, in the present study, we investigated the role of Siah2 in the IPC-induced neuroprotection in in vitro and in vivo models of IPC. To this aim, cortical neurons were exposed to 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3 h OGD plus reoxygenation (lethal insult). Our results revealed that the mitochondrial depolarization induced by hypoxia activates Siah2 at the mitochondrial level and increases LC3-II protein expression, a marker of mitophagy, an effect counteracted by the reoxygenation phase. By contrast, hypoxia reduced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a marker of mitochondrial biogenesis, whereas its expression was increased after reoxygenation thus improving mitochondrial membrane potential, mitochondrial calcium content, and mitochondrial morphology, hence leading to neuroprotection in IPC. Furthermore, Siah2 silencing confirmed these results. Collectively, these findings indicate that the balance between mitophagy and mitochondrial biogenesis, due to the activation of the Siah2-E3-ligase, might play a role in IPC-induced neuroprotection.

DOI: https://doi.org/10.1038/s41419-025-07339-z

Nat Commun. 2025 Jan 24. 16(1): 999

Diet-derived urolithin A is produced by a dehydroxylase encoded by human gut Enterocloster species.

Reilly Pidgeon, Sacha Mitchell, Michael Shamash, Layan Suleiman, Lharbi Dridi, Corinne F Maurice, Bastien Castagner.

Urolithin A (uroA) is a polyphenol derived from the multi-step metabolism of dietary ellagitannins by the human gut microbiota. Once absorbed, uroA can trigger mitophagy and aryl hydrocarbon receptor signaling pathways, altering host immune function, mitochondrial health, and intestinal barrier integrity. Most individuals harbor a microbiota capable of uroA production; however, the mechanisms underlying the dehydroxylation of its catechol-containing precursor (uroC) are unknown. Here, we use a combination of untargeted bacterial transcriptomics, proteomics, and comparative genomics to uncover an inducible uroC dehydroxylase (ucd) operon in Enterocloster species. We show that the ucd operon encodes a predicted molybdopterin-dependent enzyme complex that dehydroxylates urolithins at a specific position (9-OH). By interrogating publicly available metagenomics datasets, we observed that uroC-metabolizing Enterocloster species and ucd operon genes are prevalent in human feces. In ex vivo experiments with human fecal samples, only samples actively transcribing ucd could produce uroA, possibly explaining differences in urolithin metabolism between individuals. Collectively, this work identifies Enterocloster species and the ucd operon as important contributors to uroA production and establishes a multi-omics framework to further our mechanistic understanding of polyphenol metabolism by the human gut microbiota.

DOI: https://doi.org/10.1038/s41467-025-56266-2