Cancers relax selection on charge at the mitochondrial complex I quinone cavity

In mitochondrial complex I, cancers relax selection on charge at mtDNA-encoded ND proton-loading sites, showing enrichment up to 1.67 in tumor datasets versus depletion in germline sites.

• Why it matters: Proton transport in complex I depends on both electrostatics and hydration connectivity, but it was unclear whether these constraints are independently maintained or relaxed in disease.
• What they did: Using a 2.39 cryo-EM structure with 2,945 ordered waters, the proton wire of seven mtDNA-encoded ND subunits was modeled and 40,166 missense substitutions were scored on electrostatic shift and topological disruption axes.
• The result: Across 858 germline variant sites, loading sites (0.51) and cut vertices (0.67) were depleted, while tumors enriched only loading sites (1.42 TCGA, 1.67 PCAWG, 1.29 MSK-IMPACT), with a 3.06-fold tissue-type interaction (P = 3.6 10-).

AI summary of the abstract · may contain errors · not medical advice · read the paper.