Mitochondrial deficiency impairs hypoxic induction of HIF-1 transcriptional activity and retards tumor growth

Mitochondria can be involved in regulating cellular stress response to hypoxia and tumor growth, but little is known about that mechanistic relationship. Here, we show that mitochondrial deficiency severely retards tumor xenograft growth with impairing hypoxic induction of HIF-1 transcriptional activity. Using mtDNA-deficient rho0 cells, we found that HIF-1 pathway activation was comparable in slow-growing rho0 xenografts and rapid-growing parental xenografts. Interestingly, we found that ex vivo rho0 cells derived from rho0 xenografts exhibited slightly increased HIF-1alpha expression and modest HIF-1 pathway activation regardless of oxygen concentration. Surprisingly, rho0 cells, as well as parental cells treated with oxidative phosphorylation inhibitors, were unable to boost HIF-1 transcriptional activity during hypoxia, although HIF-1alpha protein levels were ordinarily increased in these cells under hypoxic conditions. These findings indicate that mitochondrial deficiency causes loss of hypoxia-induced HIF-1 transcriptional activity and thereby might lead to a constitutive HIF-1 pathway activation as a cellular adaptation mechanism in tumor microenvironment.

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Koido M, Haga N, Furuno A, Tsukahara S, Sakurai J, Tani Y, Sato S, Tomida A