PXD081961-1

PXD081961 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial SUMOylation of NDUFA9 Drives ClpP-Dependent Degradation and Complex I Dysfunction in a Leigh Syndrome–Associated Mutation
Description	Mitochondrial complex I (CI) is essential for mitochondrial energy metabolism, and its dysfunction underlies a large fraction of inherited mitochondrial diseases, including Leigh syndrome. However, how post-translational modifications (PTMs) govern CI subunit stability and quality control remains poorly understood. Here we identify NDUFA9, a conserved accessory subunit of CI, as a bona fide mitochondrial SUMOylation substrate. NDUFA9 is predominantly conjugated by SUMO1 at a conserved C-terminal lysine (K370), and this modification promotes its interaction with the mitochondrial protease ClpP through the SIM motifs of ClpP, thereby accelerating protease activity-dependent degradation. Functionally, K370 SUMOylation destabilizes NDUFA9, compromises fully assembled CI and CI activity, and perturbs mitochondrial bioenergetics, whereas a SUMOylation-deficient K370R mutant stabilizes NDUFA9 and preserves CI function. We further show that mitochondrial deSUMOylation by SENP2 restrains this process, defining a mitochondrial SUMO–SENP2–ClpP axis that maintains NDUFA9 proteostasis and CI integrity. Importantly, the Leigh syndrome–associated NDUFA9R321P mutation enhances binding to the SUMO E2 enzyme Ubc9, increases K370 SUMOylation, and drives excessive ClpP-dependent degradation of NDUFA9. Genetic blockade of SUMOylation at K370 restores NDUFA9 abundance, rescues fully assembled CI and CI activity, and alleviates mitochondrial dysfunction. In vivo, both systemic and brain-specific AAV-based replacement models demonstrate that R321P-induced hyper-SUMOylation causes CI deficiency and motor dysfunction, which are substantially reversed by preventing SUMOylation.
HostingRepository	iProX
AnnounceDate	2026-07-31
AnnouncementXML	Submission_2026-07-31_00:20:22.392.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jiaqian Feng
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2026-07-31 00:19:57	ID requested
⏵ 1	2026-07-31 00:20:22	announced

Dataset with its publication pending

submitter keyword: SENP2, Mitochondria, SUMO1-modified proteins

Yong Li
contact affiliation	Department of Biochemistry and Molecular Cell Biology Shanghai Jiao Tong University School of Medicine
contact email	fengjiaqian116@163.com
lab head
Jiaqian Feng
contact affiliation	Shanghai Jiao Tong University School of Medicine
contact email	fengjiaqian116@163.com
dataset submitter

iProX dataset URI