Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs

Abstract

Mitochondrial defects have long been suspected to play an important role in the development of cancer. Although most cancer cells harbor somatic mutations in mitochondrial DNA (mtDNA), the question of whether such mutations positively contribute to the development of cancer remained unclear. To clarify the role of mutant mtDNA excluding effects by the nuclear background, we focus on a method of transmitochondrial cybrids. Tumors were formed by transplanting cybrids with or without mutant mtDNA into nude mice and compared each size, revealing that mutant cybrids enhanced tumorigenesis. Next, we discuss a method for excluding the possibility of secondary nuclear mutations that may affect tumorigenesis. Mitochondrial genes that had been converted from mitochondrial to nuclear codons and equipped with a mitochondrial-targeting sequence were introduced into the nucleus of mutant cybrids. The gene products complemented the dysfunction, and reduced the promotion of tumors. By these methods, we concluded that mutant mitochondria positively and directly contribute to tumorigenesis. Since apoptosis occurred less frequently in the mutant versus wild-type cybrids in tumors, pathogenic mtDNA mutations contribute to the promotion of tumors by preventing apoptosis. Finally, we discuss the role of mutant mtDNA in conferring tolerance against anticancer drugs.