Mitochondrial DNA Mutations in Cancer

Mitochondrial defects have been associated with severe neurodegenerative disorders [2], and, more recently, with primary hereditary neoplasias. Germline heterozygote mutations in the nucleus-encoded mitochondrial succinate dehydrogenase (SDH) subunits—a tricarboxylic acid cycle (TCA) enzyme, which is also part of the respiratory chain—cause inherited pheochromocytomas and paragangliomas. Mutations in another TCA enzyme, fumarate hydratase (FH), cause cutaneous and uterine leiomyomas, as well as renal cell carcinomas [3]. Mitochondrial proteins may also play a role in the development of the sporadic kidney tumor oncocytoma [4]. Selak et al. has recently shed light on the mysterious connection between tumors and SDH/ FH [5]; they showed that the hypoxiainducible factor (HIF)–mediated signaling pathway, known to be tumorigenic in von Hippel Lindau syndrome, also plays a role in SDH and FH defi ciency (Figure 1) [5].