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.

Recent Publications Summary

Recent studies have linked mitochondrial respiratory chain complex I to disease states characterized by altered oxidative phosphorylation and mitochondrial remodeling. In high-grade serous ovarian cancer, multi-omics analyses identified a metabolically rewired chemotherapy-response subtype with heightened OXPHOS and mitochondrial remodeling; pharmacologic inhibition of complex I with IACS-010759, or genetic silencing of the core subunit NDUFA8, selectively restored carboplatin sensitivity in resistant cells and xenograft models 42474029Jul. In ER-positive breast cancer, ICAM2 was found to promote endocrine resistance by binding DYNLT3 and the complex I subunit MT-ND2, facilitating dynein-mediated mitochondrial trafficking and modulating complex I assembly; disruption of this axis suppressed OXPHOS, and combining the complex I inhibitor IACS-10759 with fulvestrant inhibited tumor growth and metastasis 42151122May.

Complex I was also associated with immunotherapy response in esophageal squamous cell carcinoma. Proteome-based stratification showed that tumors with high complex I protein expression were more sensitive to anti-PD1 therapy, and higher complex I levels in cancer cells or patient-derived organoids increased CD8+ T cell-mediated killing; inhibition of YAP1 or increasing complex I levels enhanced immunotherapy efficacy in allograft tumors 41965870Apr. These findings suggest that complex I abundance may mark, and potentially influence, an immune-responsive tumor state.

Beyond cancer, complex I-related mitochondrial dysfunction was implicated in non-malignant disease models. In renal fibrosis, integrative transcriptomic and proteomic analysis identified NDUFS8 and NDUFS2 as core targets of arctigenin, with OXPHOS as the central intersecting pathway; the authors proposed that mitochondrial pathway modulation reduced excessive reactive oxygen species production and oxidative stress 42276167Jun. In age-related cognitive decline, ATP11B deficiency was reported to induce mitochondrial respiratory dysfunction by regulating chromatin accessibility of KLF4 to mitochondrial respiratory chain complex genes, contributing to neuronal ferroptosis and aging phenotypes 42002550Apr.

Several fungicidal studies also pointed to complex I as a candidate target. Pyrimidinamine derivatives were designed as novel complex I inhibitors, and transcriptome analysis of Blumeria graminis revealed differentially expressed genes enriched in complex I-related pathways, supporting complex I as the potential target of the most active compound 42267947Jun. Similarly, indole derivatives with biphenyl and diphenyl ether moieties were studied in a fungal system, although the abstract identified mitochondrial complex III—not complex I—as the proposed target 42554814Aug.

What Changes, What Holds

1. Complex I inhibition emerges as a resistance-reversal strategy in tumors that have rewired toward OXPHOS
NEW DIRECTION Complex I now looks less like a general bioenergetic marker and more like a vulnerability that can be exploited when cancer cells become dependent on oxidative phosphorylation for drug resistance. That extends the baseline’s therapeutic framing from broad mitochondrial dysfunction to a more specific context: reversing chemotherapy or endocrine resistance by blocking complex I-dependent metabolism 42474029Jul42151122May. The two studies are directionally aligned, but still preclinical and do not yet establish which patient subsets would benefit most.

2. Complex I abundance may function as a marker of immune responsiveness rather than simply metabolic state
NEW DIRECTION High complex I expression in esophageal squamous cell carcinoma adds a new immunologic role that the Overview did not cover: it may identify tumors more likely to respond to anti-PD1 therapy and may even help shape that response through better CD8+ T cell killing 41965870Apr. This does not contradict the baseline, which already noted immunotherapy relevance, but it shifts attention from mere association to a potential biomarker-and-mechanism axis. Causality and clinical utility remain unsettled.

3. Complex I-linked mitochondrial dysfunction is now implicated in fibrosis and cognitive decline mechanisms outside the baseline’s cancer-heavy focus
NEW DIRECTION Arctigenin’s targeting of NDUFS8 and NDUFS2 in renal fibrosis extends complex I biology into a mechanistic antioxidant/antifibrotic frame, while ATP11B deficiency links mitochondrial respiratory chain gene regulation to neuronal ferroptosis and aging phenotypes 42276167Jun42002550Apr. The Overview already mentioned renal fibrosis, but not this specific complex I-centered pathway; it said nothing about cognitive decline, so that part is a new role. Both findings are hypothesis-generating and need functional validation.

4. Complex I remains a plausible fungicidal target, while one candidate series points elsewhere
REINFORCES Pyrimidinamine derivatives and the associated transcriptomic signal strengthen the idea that mitochondrial complex I can be a viable antifungal target, fitting the broader baseline theme that complex I disruption can have major biological effects 42267947Jun. The indole series cuts across that only superficially: because the abstract names complex III instead of complex I, it does not add evidence for complex I itself. Taken together, the paragraph mostly confirms targetability and also shows that not every mitochondrial-acting compound in this space hits complex I.

Overview update candidates: complex I as a resistance-reversal target in OXPHOS-rewired Cancers; complex I abundance as a biomarker and possible mediator of immunotherapy response; complex I-linked mitochondrial dysfunction in renal fibrosis and age-related cognitive decline; complex I as a candidate fungicidal target.