The role of mitochondrial electron transport in tumorigenesis and metastasis

• Published in: Biochimica et biophysica acta Vol. 1840; no. 4; pp. 1454 - 1463
• Main Authors: Tan, An S., Baty, James W., Berridge, Michael V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2014
• Subjects: Animals; blood; carcinogenesis; Carcinogenesis - genetics; electron transfer; Electron Transport - genetics; energy; energy metabolism; epigenetics; glycolysis; Humans; lymphatic system; Metabolic flexibility; Metastasis; mitochondria; Mitochondria - genetics; Mitochondrial electron transport; mitochondrial genome; Mitochondrial mutation; Mitochondrial respiration; Mutation; neoplasm cells; Neoplasm Metastasis - genetics; neoplasms; phenotype; stromal cells; Tumor Microenvironment; Tumorigenesis; Mitochondrial respiration; Tumorigenesis; Metastasis; Metabolic flexibility; Mitochondrial electron transport; Mitochondrial mutation
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.10.016

Tumor formation and spread via the circulatory and lymphatic drainage systems is associated with metabolic reprogramming that often includes increased glycolytic metabolism relative to mitochondrial energy production. However, cells within a tumor are not identical due to genetic change, clonal evolution and layers of epigenetic reprogramming. In addition, cell hierarchy impinges on metabolic status while tumor cell phenotype and metabolic status will be influenced by the local microenvironment including stromal cells, developing blood and lymphatic vessels and innate and adaptive immune cells. Mitochondrial mutations and changes in mitochondrial electron transport contribute to metabolic remodeling in cancer in ways that are poorly understood. This review concerns the role of mitochondria, mitochondrial mutations and mitochondrial electron transport function in tumorigenesis and metastasis. It is concluded that mitochondrial electron transport is required for tumor initiation, growth and metastasis. Nevertheless, defects in mitochondrial electron transport that compromise mitochondrial energy metabolism can contribute to tumor formation and spread. These apparently contradictory phenomena can be reconciled by cells in individual tumors in a particular environment adapting dynamically to optimally balance mitochondrial genome changes and bioenergetic status. Tumors are complex evolving biological systems characterized by genetic and adaptive epigenetic changes. Understanding the complexity of these changes in terms of bioenergetics and metabolic changes will permit the development of better combination anticancer therapies. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. Metabolic remodeling involves integration of multiple microenvironmental and adaptive inputs. Adaptation to changes in the local tumor microenvironment including essential nutrients, bioenergetics fuels and oxygen supply involve nuclear and mitochondrial mutations, intercellular mitochondrial trafficking and epigenetic changes. Integration of these changes will result in a window of opportunity for tumor progression around a bioenergetics and metabolic optimum that we refer to as the sweet spot. [Display omitted] •Mitochondrial electron transport is required for tumor formation and metastasis•mtDNA mutations can contribute to tumor formation and progression•Genetic and epigenetic changes dictate optimal bioenergetic status of tumor cells•Local tumor cell survival is constrained by mitochondrial respiratory function•Changes in the microenvironment require bioenergetic and metabolic flexibility