Mitochondrial respiratory chain complex I
Mitochondrial respiratory chain complex I
Overview
Mitochondrial respiratory chain complex I, also known as NADH:ubiquinone oxidoreductase, is the first and one of the largest enzyme complexes of the mitochondrial oxidative phosphorylation system. It catalyzes electron transfer from NADH to ubiquinone and contributes to the proton gradient that drives ATP synthesis. Because of this central role in mitochondrial bioenergetics, complex I is a major determinant of cellular energy production, redox balance, and susceptibility to oxidative stress.
In biomedical research, complex I is frequently studied as both a functional readout of mitochondrial health and a therapeutic target. Altered complex I activity has been linked in the provided studies to renal fibrosis, neurodegeneration, endocrine resistance in breast cancer, immunotherapy response in esophageal squamous cell carcinoma, pediatric acute myeloid leukemia, and mitochondrial dysfunction in immune cells. The entity is also relevant in plant biology, where disruption of mitochondrial complex I-related pathways can affect growth and development.
Focus of Latest Publications
Recent publications have continued to position mitochondrial respiratory chain complex I as a key metabolic node in disease biology and therapeutic response. In renal fibrosis, multi-omics profiling of a unilateral ureteral obstruction rat model identified the complex I subunits NDUFS8 and NDUFS2 as core targets of arctigenin, the main active component of burdock seed. The study linked these targets to the oxidative phosphorylation pathway and reported that arctigenin restored complex I activity, reprogrammed mitochondrial energy metabolism, and reduced excessive reactive oxygen species production and oxidative stress, thereby attenuating fibrotic progression.
Several studies also explored complex I as a drug target in cancer and infectious disease. In esophageal squamous cell carcinoma, proteomic, phosphoproteomic, and immunohistochemical analyses of treatment-naïve patients receiving anti-PD1 immunotherapy showed that high mitochondrial complex I protein expression was associated with sensitivity to immunotherapy and enhanced CD8+ T cell-mediated killing in co-culture systems. The same study reported that YAP1 activation impaired immunotherapy efficacy, while increasing complex I levels or inhibiting YAP1 improved anti-tumor responses in allograft tumors. In pediatric acute myeloid leukemia, patient-derived xenograft models supported mitochondrial targeting as a therapeutic strategy: the complex I inhibitor IACS-010759, combined with venetoclax, reduced disease progression in KMT2A-rearranged models, including relapse settings.
Other publications focused on complex I as a biomarker or putative target rather than a direct therapeutic intervention. In endocrine-resistant ER-positive breast cancer, multi-omics analyses identified ICAM2-positive cells as a high-OXPHOS population and showed that ICAM2 interacts with dynein light chain DYNLT3 and the mitochondrial complex I subunit MT-ND2, promoting mitochondrial trafficking and complex I assembly. Disrupting this axis with ICAM2 knockdown or dynein inhibition suppressed oxidative phosphorylation, and combining IACS-10759 with fulvestrant inhibited tumor growth and metastasis. In a fungicidal discovery study, pyrimidinamine derivatives were designed as novel complex I inhibitors; transcriptome analysis of Blumeria graminis suggested enrichment of differentially expressed genes in complex I-related pathways, supporting complex I as the likely target of the most active compound.
Methodological studies also noted complex I in the context of proteome coverage. A streamlined tissue proteomics workflow for fresh-frozen and formalin-fixed paraffin-embedded samples reported that preservation-related effects reduced detection of membrane-associated and respiratory proteins, including mitochondrial complex I. Together, these publications highlight complex I as a recurring focus in studies of mitochondrial metabolism, fibrosis, cancer immunotherapy, antifungal development, and translational proteomics.