bims-mitpro 2026-09-06 papers

Issue of 2026–09–06
five papers selected by
Andreas Kohler, Umeå University

Nat Struct Mol Biol. 2026 Aug 31.

A single-amino-acid cleavage controls global mitochondrial complex integrity.

Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle.

Mitochondrial proteostasis depends on precise N-terminal processing of imported precursor proteins. Defects in this maturation step are implicated in disease, yet the functional impact in humans remains unclear. Here we show that the intermediate cleaving peptidase ICP55, which removes a single amino acid, acts as a key stabilizer of multimeric mitochondrial protein complexes. Using proteomics and complexome profiling, we identify over 100 human ICP55 substrates and demonstrate that loss of ICP55 triggers widespread destabilization of protein assemblies, with a global shift toward smaller subcomplexes. Thus, we uncover a conserved, post-translational mechanism that safeguards mitochondrial proteostasis by regulating complex integrity through a single amino-acid cleavage, and we reveal N-terminal proteoform control as an unexpected layer of organellar homeostasis.

DOI: https://doi.org/10.1038/s41594-026-01876-7

Autophagy. 2026 Sep 01.

RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.

Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano.

Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the de novo synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.

Keywords: Autophagy; Optineurin; PINK1; Parkin; RAB GTPase; mitochondria; ubiquitin

DOI: https://doi.org/10.1080/15548627.2026.2728346

Antioxid Redox Signal. 2026 Sep 02. 15230864261481794

Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.

Huijia Zhang, Ying Chen, Junjie Jiang, Yarong Ding, Si Hu, Zhongzhi Zhou, Li Chen.

Background:Mitochondrial quality control has traditionally been attributed to mitophagy. However, emerging evidence indicates that mitochondrial microautophagy represents a distinct quality control pathway. This pathway enables selective removal of damaged mitochondrial subdomains while preserving overall organelle integrity. Therefore, mitochondrial microautophagy can be viewed as a redox-adaptive, sub-organelle quality control system that responds to localized mitochondrial stress.Scope of Review: In this review, we integrate recent mechanistic, imaging, and molecular studies to establish an updated framework of mitochondrial microautophagy. We describe this process as a sequential pathway involving damage sensing, mitochondria-lysosome contact formation, lysosomal membrane remodeling, selective degradation, and metabolic recycling. Localized reactive oxygen species (ROS) serve as important signals during this process. ROS define specific damage microdomains and facilitate selective mitochondrial component recognition. Subsequent cargo delivery and degradation are regulated by multiple molecular modules. These modules include the ubiquitin-autophagy-related protein 8 system, vacuolar-type H+-ATPase-dependent membrane remodeling, Ras-related in brain-endosomal sorting complexes required for transport signaling, the spermatogenesis-associated 18/mitochondria-eating protein pathway, and the mechanistic target of rapamycin complex 1-transcription factor EB and nuclear factor erythroid 2-related factor 2 stress-response networks.Outstanding Questions: Despite substantial progress, several fundamental questions remain unresolved. The mechanisms underlying cargo recognition require further clarification. The existence of specific redox-sensitive receptors remains to be determined. In addition, future technological advances will provide deeper insights into this pathway.Conclusions: Understanding mitochondrial microautophagy may reveal new therapeutic opportunities for mitochondrial dysfunction-associated disorders, including neurodegeneration, ischemic injury, metabolic disorders, and aging. Antioxid. Redox Signal. 00, 000-000.

Keywords: ESCRT complex; Rab GTPase; SPATA18/Mieap; TFEB; V-ATPase; autophagy; lysosomal membrane remodeling; mitochondrial microautophagy; mitochondrial quality control

DOI: https://doi.org/10.1177/15230864261481794

NPJ Dement. 2026 ;2(1): 83

Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.

Shatakshi Shukla, Devin Kolmetzky, Shanikumar Goyani, Kunal Samantaray, Anupriya Sinha, Philip A Kramer, Dhanendra Tomar, Pooja Jadiya.

Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPRmt) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPRmt-MM) and IMS (UPRmt-IMS) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPRmt-MM promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPRmt-IMS preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPRmt signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.

Keywords: Cell biology; Molecular biology; Neuroscience

DOI: https://doi.org/10.1038/s44400-026-00137-0

Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930

MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.

Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.

Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.

Keywords: CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage

DOI: https://doi.org/10.1016/j.celrep.2026.117930