Mitochondrial inhibitory factor protein 1 attenuates coupling factor 6‐induced aging signal

Coupling factor 6 (CF6) forces a counter‐clockwise rotation of plasma membrane F1Fo complex, resulting in proton import and accelerated aging. Inhibitory factor peptide 1 (IF1) suppresses a unidirectional counter‐clockwise rotation of F1Fo complex without affecting ATP synthesis. We tested the hypothesis that IF1 may attenuate CF6‐induced aging signaling in CF6‐overexpressing transgenic (TG) cells. In IF1‐GFP overexpressing wild type (WT) cells, the diffuse peripheral staining of tubular mitochondria was observed with a dense widely distributed network around the nucleus. In TG cells, however, the only peri‐nuclear network of fragmented mitochondria was observed at 24 h, but it was developed to a widely distributed mitochondrial network of tubular mitochondria at 72 h. TG cells displayed aging hallmarks of telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability with a decrease in emerin and lamin and loss of heterochromatin. IF1 induction rescued TG cells from telomere attrition, expression of genomic instability with the increase in emerin and lamin, and that of epigenetic alterations with recovery of heterochromatin. In defective proteostasis, IF1 induction restored a potent peri‐nuclear staining of autolysosomes compared with the baseline weak staining. The decrease in Atg7 was restored, whereas the increase in P62 was abolished. We conclude that genetic disruption of proton signals by IF1 induction suppressed CF6‐induced expression of aging hallmarks such as telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability. Given the widespread biological actions of CF6, the physiological and pathological actions of IF1 may be complex. We tested the hypothesis that IF1 may attenuate coupling factor 6 (CF6)‐induced aging signaling in CF6‐overexpressing transgenic (TG) cells. Genetic disruption of proton signals by IF1 induction suppressed CF6‐induced expression of aging hallmarks such as telomere attrition, epigenetic alterations, defective proteostasis, and genomic instability. Given the widespread biological actions of CF6, the physiological and pathological actions of IF1 may be complex.