bims-tofagi 2026-01-25 papers

Issue of 2026–01–25
six papers selected by
Michele Frison, University of Cambridge

NPJ Aging. 2026 Jan 22.

Parkin deficiency impairs female fertility, oocyte development, fertilization and mitochondrial function in mice.

Michelle Volovsky, Adolfo Rodríguez-Eguren, Yagmur Ergun, Raziye Melike Yildirim, Gizem Nur Sahin, Rolando Garcia Milian, Sameet Mehta, Lavinia Turanli, Irene Cervelló, Richard Scott, Emre Seli.

Parkin, a mitochondrial E3 ubiquitin ligase, plays a central role in mitophagy and cellular homeostasis. Although well studied in neurobiology, its role in female reproduction remains unclear. This study investigated the role of Parkin on female fertility using young (2-3 months old) and older (9-10 months old) mice with a global germline Parkin deletion. Parkin knockout (KO) females exhibited significantly reduced fertility with total pups per female lower in KO mice (16.0 ± 1.53) compared to wild type (WT) (22.33 ± 0.67; p = 0.02). In young mice, GV oocyte yield was significantly reduced in KO (30.0 ± 1.53) compared to WT (52.7 ± 6.96; p = 0.03), as was MII oocyte count (7.7 ± 0.67 vs. 22.3 ± 0.88; p = 0.0002). In older mice, similar trends were observed. Fertilization rates were significantly lower in KO mice compared to WT (36.2 ± 8.1% vs. 61.2 ± 5.5%; p = 0.03). RNA sequencing identified multiple differentially expressed genes between KO and WT, with associated pathway changes. These findings indicate that Parkin deficiency impairs oocyte yield, fertilization capacity, and overall fertility, suggesting that Parkin plays a key role in reproductive competence.

DOI: https://doi.org/10.1038/s41514-026-00332-6

Nat Plants. 2026 Jan 21.

ATG5-HSP90.2-mediated micromitophagy as a cytological basis for maternal inheritance of plant mitochondria.

Xiaorong Huang, Linlin Zhao, Zonglin Liu, Ni Long, Wenxuan Zou, Feng Gong, Tianhe Cheng, Ce Shi, Xuecheng Zhang, Wei Wang, Hong Chen, Alice Y Cheung, Meng-Xiang Sun.

Mitochondria are inherited maternally in most plants as a classical paradigm of non-Mendelian inheritance, but the mechanism underlying paternal mitochondrial elimination (PME) remains almost unknown. We report here that angiosperms have evolved micromitophagy-mediated PME, in which vacuoles directly engulf paternal mitochondria via tonoplast invagination. We show that micromitophagy occurs specifically in male germline (MG) cells. To gain mechanistic insights, we used a vegetative-to-germline cell fate transition system to establish that micromitophagy is triggered by MG cell fate determination. We found evidence that ATG5 is translocated to vacuoles upon MG-cell-fate determination and interacts with mitochondrion-located HSP90.2 during mitochondrial engulfment by vacuoles, elucidating a cell-type-specific ATG neofunctionalization to mediate micromitophagy. This mechanism not only contributes to maternal inheritance of plant mitochondria but also supports the zygote-to-embryo transition. We further determined that micromitophagy is conserved in angiosperms but was continually optimized during evolution to support the best functioning of PME in MG cells with different properties. These findings bridge a long-standing gap in understanding plant PME with emerging mechanistic knowledge.

DOI: https://doi.org/10.1038/s41477-025-02216-1

Cell Rep. 2026 Jan 17. pii: S2211-1247(25)01627-4. [Epub ahead of print]45(1): 116855

Stuxnet balances mitochondria homeostasis by regulating uhg5 and parkin.

Xianguo Zhao, Xingzhuo Yang, Yuansheng Huang, Yifan Zhang, Xiangzhou Cui, Junzheng Zhang, Juan Du.

Emerging evidence implicates the Stuxnet (Stx) protein in human disease, extending beyond its known role in proteasome-independent degradation. Exploring this further, our investigation into stx downstream targets in Drosophila reveals that loss of the U snoRNA host gene 5 (Uhg5) gene disrupts sleep. This sleep phenotype is linked to inefficient translation of mitochondrial genes, as Uhg5 produces small nucleolar RNAs (snoRNAs) that directly regulate mitochondrial transcripts. Using GoldCLIP technology, we discover that Stx interacts with both Uhg5 and parkin mRNAs. parkin is a key regulator of mitochondrial quality control. Genetic tests confirm functional relationships between stx, Uhg5, and parkin. This study establishes that Uhg5-derived snoRNAs regulate sleep by controlling mitochondrial gene translation. Crucially, our findings propose a model in which Stx coordinates mitochondrial biogenesis (via Uhg5) with mitophagy (via parkin). This provides a molecular link for Stx's potential role in Parkinson's disease pathogenesis.

Keywords: CP: molecular biology; CP: neuroscience; Drosophila; RNA binding protein; Uhg5; midnolin; mitochondria; mitochondrial gene translation; parkin; sleep; snoRNA host genes; stuxnet

DOI: https://doi.org/10.1016/j.celrep.2025.116855

Redox Biol. 2026 Jan 17. pii: S2213-2317(26)00027-3. [Epub ahead of print]90 104029

Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.

Wenqi Cui, Tianlu Wang, Juan Feng.

Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP+-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP+-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy.

Keywords: GBP2; Geranylgeranylation; Mitochondrial dysfunction; Mitophagy; NIX; Parkinson's disease

DOI: https://doi.org/10.1016/j.redox.2026.104029

Autophagy. 2026 Jan 22.

C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.

Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.

Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.

Keywords: Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy

DOI: https://doi.org/10.1080/15548627.2026.2621110

Autophagy. 2026 Feb;22(2): 235-237

Acetyl-CoA as a metabolic switch for selective mitophagy.

Daolin Tang, Rui Kang, Daniel J Klionsky.

A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.

Keywords: Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy

DOI: https://doi.org/10.1080/15548627.2025.2593032