bims-mitpro 2026-06-14 papers

Issue of 2026–06–14
four papers selected by
Andreas Kohler, Umeå University

Autophagy. 2026 Jun 13.

MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.

Ming-Hua Wu, Xue-Ming Zhu, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.

Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in Magnaporthe oryzae remains poorly understood. In our recent study, we found that upon outer mitochondrial membrane disruption, inner mitochondrial membrane (IMM) protein MoCox6 is rendered available for engagement with cytosolic MoAtg5 and MoAtg14 to drive mitophagy, whereas MoSirt5-mediated desuccinylation of MoCox6 at K144 weakens these interactions and thereby restrains mitophagic flux. Further analyses identified Asp95 at the MoSirt5-MoCox6 interface as a pivotal residue coupling mitochondrial metabolic control to mitophagy. A high-throughput virtual screening targeting an Asp95-centered pocket in MoCox6 identified Pan-RAS-IN-1, a small molecule that effectively suppresses rice blast incidence and exhibits broad-spectrum antifungal activity. Collectively, these findings identify MoCox6 as an IMM regulator of mitophagy whose succinylation state links mitochondrial metabolic cues to mitochondrial turnover, while highlighting mitochondrial quality control as a potential target for fungal disease management.

Keywords: Fungicide target; MoCox6; magnaporthe oryzae; mitophagy; succinylation

DOI: https://doi.org/10.1080/15548627.2026.2689458

Nat Commun. 2026 Jun 10.

A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.

Sarin Segev-Nakar, Itay Koren.

Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.

DOI: https://doi.org/10.1038/s41467-026-74117-6

Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):

CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.

Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.

Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.

DOI: https://doi.org/10.1038/s41467-026-74080-2

Autophagy. 2026 Jun 13.

STING1 senses mitochondrial damage to promote mitophagy.

Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.

The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.

Keywords: Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control

DOI: https://doi.org/10.1080/15548627.2026.2689463