Mitochondrial COX4-1 deficiency leads to impaired nuclear DNA damage response resulting in proliferation deficits and premature senescence

Cytochrome- c- oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4), who presented with bone-marrow failure, genomic instability and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated reduced proliferation and premature senescence in this patient’s fibroblasts and in COX4-1 knockdown cells. Accumulative DNA damage coincided primarily with proliferative cells, indicating replicative stress. Expression analysis implicated DNA damage response which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. Interestingly, our in-vitro findings recapitulate the patient’s presentation and present status. Thus, we suggest that the premature senescence, resulting from accumulative DNA damage in COX4-1 deficiency is a protective mechanism to avoid malignant transformation in a similar manner to what was reported for FA and other “accelerated aging diseases”.