bims-tofagi 2025-06-15 papers

Issue of 2025–06–15
two papers selected by
Michele Frison, University of Cambridge

Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00460-5. [Epub ahead of print]

Mitochondrial fumarate inhibits Parkin-mediated mitophagy.

Su Jin Ham, Sunhoe Bang, Daihn Woo, Jae-Yoon Jo, Takwon Yoo, Eunju Yoon, Yeonju Kyoung, Daehyun Baek, Jong-Seo Kim, Jongkyeong Chung.

Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology.

Keywords: ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination

DOI: https://doi.org/10.1016/j.molcel.2025.05.021

Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]

Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.

Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.

Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.

Keywords: cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells

DOI: https://doi.org/10.1016/j.cell.2025.05.020