bims-tofagi 2026-01-18 papers

Issue of 2026–01–18
five papers selected by
Michele Frison, University of Cambridge

NPJ Parkinsons Dis. 2026 Jan 15.

UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson's disease.

Jeng-Lin Li, Shu-Yi Huang, Po-Yu Huang, Ssu-Ju Fu, Yu-Jung Tsao, Wenying Chang, Cheng-Li Hong, Yu-Chien Hung, Pei-Han Liu, Liang-Chuan Lai, Chin-Hsien Lin, Wei-Chung Chiang, Chih-Chiang Chan.

Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson's disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.

DOI: https://doi.org/10.1038/s41531-026-01262-6

FASEB J. 2026 Jan 31. 40(2): e71460

AMPK Modulates the Interplay Between PINK1/Parkin-Mediated Mitophagy and NLRP3-Driven Inflammation in Diabetic Periodontal Tissue Under Mechanical Loading.

Shuo Chen, Ruijiao Yan, Yiling Chen, Shushu He, Chenchen Zhou, Shujuan Zou, Yuyu Li.

Mechanical force induces a series of biological responses such as inflammation in force-loaded tissues and cells. The periodontal ligament (PDL) fibroblasts act as vital sensors and transducers in response to mechanical loading within periodontium. Studies have shown that PDL fibroblasts also participate in mediating periodontal inflammatory responses under physiological or pathological conditions. Mitophagy is a selective form of autophagy that eliminates damaged or dysfunctional mitochondria to maintain cellular health. It plays a vital role in inflammation alleviation, cell survival, and tissue homeostasis. However, whether mitophagy is involved in mechanical force-related inflammation and the precise mechanisms remain unclear. In addition, the elucidation of the interplay between mitophagy and periodontal inflammation during mechanical loading is of great significance for maintaining periodontal homeostasis under systemic conditions. In our study, we first focused on validating the crosstalk between mitophagy and inflammation in PDL fibroblasts under mechanical loading and aimed to elucidate the upstream regulatory role of adenosine monophosphate-activated protein kinase (AMPK). Moreover, based on both in vivo and in vitro experiments, we found that high glucose conditions exacerbated inflammation by suppressing mitophagy. Additionally, targeted activation of AMPK enhanced mitochondrial turnover through mitophagy, thereby disrupting proinflammatory cascades and offering a promising strategy for inflammation resolution in periodontal diseases, especially those combined with diabetic conditions.

Keywords: AMPK activation; inflammation; mechanical loading; mitophagy; periodontal ligament fibroblasts

DOI: https://doi.org/10.1096/fj.202502330R

Sci Adv. 2026 Jan 16. 12(3): eadz2785

Reversible phase dynamics of PsAF5 regulate mitophagy to balance redox levels in Phytophthora sojae.

Jinzhu Chen, Wenhao Li, Qin Peng, Hongwei Zhu, Tan Dai, Jianqiang Miao, Xili Liu.

Redox balance is essential for normal cellular functions. PsAF5, a FYVE domain-containing protein, functions as an essential sensor and adapter, particularly in mitophagy triggered by reactive oxygen species in Phytophthora sojae. However, the regulatory role of PsAF5 in maintaining the dynamic equilibrium of the intracellular redox state has not yet been fully elucidated. Here, we identify that specific cysteine residues in the FYVE domain of PsAF5 sense cellular redox states to form and resolve disulfide bonds in a redox-dependent manner. Under reducing conditions, PsAF5 undergoes redox-dependent phase separation to form cytoplasmic condensates that are functionally decoupled from mitophagy execution. Under oxidative conditions, PsAF5 exhibits increased cytosolic solubility and enhanced interaction with PsATG8, thereby promoting mitophagy. This mechanism enables P. sojae to toggle between "detoxification" (oxidizing stress) and "metabolic resilience" (reducing stress) states, ensuring survival across hostile host niches.

DOI: https://doi.org/10.1126/sciadv.adz2785

Nat Cell Biol. 2026 Jan 12.

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.

Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.

DOI: https://doi.org/10.1038/s41556-025-01854-z

EMBO Rep. 2026 Jan 13.

Mitochondrial fission during mitophagy requires both inner and outer mitofissins.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Shun-Ichi Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Nobuo N Noda, Tomotake Kanki.

Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.

Keywords: Atg44; Mfi2; Mitochondrial Fission; Mitofissin; Mitophagy

DOI: https://doi.org/10.1038/s44319-025-00689-x