Mitochondria active species, and tumor proliferation

GALLI S; CARRERAS MC; PODEROSO JJ

Creta, Grecia

Congreso; 9th World Congress on Advances in Oncology and 7th International Symposium on Molecular Medicine; 2004

It has been proposed that a deregulation of proliferation, together with an acquired resistance towards apoptosis is a hallmark of most, perhaps all, types of cancer. Mitochondria contain the central pathway for energy metabolism but also participate in the production of O2 active species, cell cycle regulation, apoptosis and thermogenesis. The promotion of proliferation eventually entails a controlled inhibition of mitochondrial respiration. In support, most activities of tumoral and proliferating normal mitochondria are uniformly maintained at 20-30% if those of quiescent organelles. In connection with down- regulated electron transfer, proliferating and tumor mitochondria retain only 20-50% of the maximal hydrogen peroxide (H2O2) production rate of adult organelles. Likewise, low electron transport- coupled ATP synthesis correlates with faster tumor growth and high invasive behaviour. Classically, regulation of mitochondrial energy functions was based upon ADP/ ATP ratio, which dynamically stimulates the transition between resting and maximal O2 uptake. In the last years however, nitric oxide (NO) was identified as a physiologic regulator of electron transfer chain and ATP synthesis by acting on cytochrome oxidase; additionally, NO stimulates the mitochondrial production of O2 active species and depending on its matrix concentration is followed by formation of peroxinitrite (ONOO-) and nytrosilation/ nitration of mitochondrial components. Recent studies propose a common molecular and biological features between tumoral and embryonic tissues. In both conditions, NO restricts energy output, further increases O2 active speces and drives cell signaling for proliferation and apoptosis through redox effects on the specific pathways. Our results indicate that increasing mitochondrial NO and H2O2 yield is required in the transition from tissue proliferation to quiescence and that, restriction of the specific mitochondrial pathways may contribute to enduringly  deregulate tumor proliferation. In this context, our studies analyze for the first time, a putative role of mitochondrial nitric oxide synthase in cancer.