Free Radical Biology & Medicine, Vol. 8, pp. 523-539, 1990 0891-5849/90 $3.00 + .00 Printed in the USA. All fights reserved. © 1990 Pergamon Press plc Hypothesis Paper I MITOCHONDRIAL MUTATIONS MAY INCREASE OXIDATIVE STRESS: IMPLICATIONS FOR CARCINOGENESIS AND AGING.'? BRIAN BANDY* and ALLAN J. DAVISON Bioenergetics Research Laboratory, School of Kinesiology, Simon Fraser University, Bumaby, B.C., Canada V5A 1S6; Environmental Carcinogenesis Unit, B.C. Cancer Research Center, 601 W 10th Ave., Vancouver, B.C., Canada V5Z 1L3 (Received 15 September 1989; Revised and Accepted 22 February 1990) Abstract--The sensitivity of mitochondrial DNA to damage by mutagens predisposes mitochondria to injury on exposure of ceils to genotoxins or oxidative stress. Damage to the mitochondrial genome causing mutations or loss of mitochondrial gene products, or to some nuclear genes encoding mitochondrial membrane proteins, may accelerate release of reactive species of oxygen. Such aberrant mitochondria may contribute to cellular aging and promotion of cancer. Keywords--Mitochondrial mutations, Oxidative stress, Carcinogenesis, Cellular aging, Mitochondrial respiration, Superoxide, Lipid peroxidation, Intracellular calcium, Free radicals INTRODUCTION Not all mitochondrial abnormalities in cancer cells resuh from ischemia Mitochondrial abnormalities in cancer cells are many. These abnormalities include1.2: 1. changes in ultrastucture; 2. deficiencies in energy-linked functions (such as ADP-stimulated state III respiration); 3. increased state IV (ADP-limited) respiration; 4. loss of ability to undergo swelling and ATP-in- duced contraction cycles; 5. disturbed Ca 2+ or K + transport; 6. impaired protein synthesis, and 7. loss of electron transport components. Warburg wrote3: "Cancer arises because lack of ox- ygen, or respiratory enzymes, produces fermentation in the body cells and leads to a destruction of the differentiation of these cells." For many years cancer research focused on the loss of respiratory metabolism common to tumor cells. Tumor cells are not always grossly impaired in respiration however, and the con- nections between mitochondrial function or dysfunc- tion and neoplasia (e.g., activation of nuclear oncogenes) are not obvious. Mitochondrial aberrations *Author to whom correspondence should be addressed. may be attributed to the poor perfusion and anoxic state of many tumors. Mitochondrial aberrations in cancer cells which are not ischemic however, such as the leu- kemias, 4 or ascites, or cultured tumor cells, of ~require other explanations. Recent reports that mitochondrial DNA is highly sensitive to mutagens and that cyto- plasm transfer supresses tumorigenicity, has prompted suggestions of a more direct role of mitochondria in transformation.2"5-1J Impaired calcium regulation,2.8 or incorporation of mitochondrial DNA fragments into the nuclear genome 9,1~ are two suggested mechanisms by which mitochondria might contribute to neoplastic transformation. Release of active oxygen by mitochondria may promote transformation The possibility that mitochondria contribute to tu- morigenesis as an intracellular source of excited ox- ygen deserves consideration. Reactive species of oxygen can participate in the initiation or promotion of cancer through their ability to cause point mutations, DNA cross-links, and DNA strand breaks in nuclear chromosomes. Such injuries may activate an oncogene or inactivate a tumor-suppressor gene. Mitochondria consume over 90% of the oxygen used by most cells and are a significant source of active oxygen under normal conditions. Any condition which increases this generation, or decreases protective systems, will likely 523