Mitochondria and Cancer

Abstract

Decades ago, Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events that drive aberrant cancer cell proliferation also alter biochemical metabolism, including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy; provide building blocks for new cells; and control redox homeostasis, oncogenic signaling, innate immunity, and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mtDNA limits tumorigenesis, and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multifunctional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

Figure 1. Mitochondria as biosynthetic and signaling hubs

The TCA cycle uses substrates from glycolysis, fatty acid oxidation, and amino acid catabolism to generate building blocks and high-energy electrons (NADH and FADH₂) to power the ETC. Major biosynthetic products produced by mitochondria and signaling pathways regulated by mitochondrial function are indicated.

Figure 2. Characteristics of oncocytic (mitochondria-rich) tumors with functional versus defective mitochondria