BBB Seminar: Rodrigue Rossignol

Rodrigue Rossignol
Laboratory of Rare Diseases: Genetics and Metabolism (MRGM), University of Bordeaux, France

Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are part of a greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored and it has become critical to decipher the stimuli and the underlying molecular pathways. We were the first to describe the enhancement of mitochondrial form and function in cancer cells forced to survive in aglycemia as occurs in solid tumors. Such adaptation includes shape changes of the mitochondrial tubules with increased expression of respiratory chain proteins. Using label-free proteomics we observed a shift of energy producing pathways toward amino acid degradation, ketogenesis and unconventional oxidative phosphorylation (OXPHOS). This shift was associated with a broader signature of cancer cell transformation, including changes in immunogenicity, cell adhesion and antioxidant defenses. These findings demonstrate that mitochondria are not defective in cancer cells and suggest the existence of oxidative tumors in contrast to Warburg’s hypothesis. In agreement with this view we found a class of human lung tumors with a high OXPHOS activity as compared to the surrounding non-cancer tissue. We propose therefore that research on mitochondrial adaptation and transformation could allow the design of innovative therapies, notably in cancer.

Key references:

Benard, G., N. Bellance, et al. (2007). "Mitochondrial bioenergetics and structural network organization." J Cell Sci 120:838-48.

Benard, G., F. Massa, et al. (2012). "Mitochondrial CB(1) receptors regulate neuronal energy metabolism." Nat Neurosci 15:558-64.

Benard, G., T. Trian, et al. (2012). "Adaptative capacity of mitochondrial biogenesis and of mitochondrial dynamics in response to pathogenic respiratory chain dysfunction." Antioxid Redox Signal [ahead of print].

Rezvani, H. R., A. L. Kim, et al. (2011). "XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas." J Clin Invest 121:195-211.

Rossignol, R. (2011). "Bioenergetics of cancer. Foreword." Biochim Biophys Acta 1807:533.

Rossignol, R. (2013). "The expanding universe of mitochondrial research." Int J Biochem Cell Biol 45:2-3.

Rossignol, R., B. Faustin, et al. (2003). "Mitochondrial threshold effects." Biochem J 370:751-62.

Rossignol, R., R. Gilkerson, et al. (2004). "Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells." Cancer Res 64:985-93.

Rossignol, R. and M. Karbowski (2009). "Editorial of the directed issue on mitochondrial dynamics in biology and medicine." Int J Biochem Cell Biol 41:1748-9.

Rossignol, R., T. Letellier, et al. (2000). "Tissue variation in the control of oxidative phosphorylations: implication for mitochondrial diseases." Biochem J 347:45-53.

Rossignol, R., M. Malgat, et al. (1999). "Threshold effect and tissue specificity. Implication for mitochondrial cytopathies." J Biol Chem 274:33426-32.

Trian, T., G. Benard, et al. (2007). "Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma." J Exp Med 204:3173-81.

Host: Karl Johan Tronstad, Department of Biomedicine