Retrograde Regulation Due to Mitochondrial Dysfunction May Be an Important Mechanism for Carcinogenesis

Mitochondrial dysfunction has crucial importance in carcinogenesis. Due to several reasons, it may lead to insufficiency in the electron transport chain, which activates a series of cytosolic proteins. These proteins are transported to the nucleus and promote the activation of genes leading to intracellular diverse metabolic, regulatory, signalization and stress-related pathways. Retrograde regulation is the general term for mitochondrial signaling, and is broadly defined as cellular responses to alterations in functional state of mitochondria. This signaling pathway is triggered by mitochondrial dysfunction. The retrograde response is not a simple On-Off switch, but rather it responds in a continuous manner to the changing metabolic needs of the cell. Communication between mitochondria and the nucleus is important for a variety of cellular processes such as carbohydrate and nitrogen metabolism, cell cycle and proliferation, and cell growth and morphogenesis. As a result of retrograde regulation, the cell, actually a component of the multicellular organism, transforms to a unicellular lifestyle and initiates a developing course, independent of the systemic structure. This transformed cell runs metabolic regulations effectively in order to utilize all energy depots, mainly the adipose tissue of the multicellular organism. The most important one is the active utilization of glyoxylate cycle, through which the malign cells supply glucose from fats. Continuously acting glycolysis and gluconeogenesis, fatty acid oxidation and de novo lipogenesis constitute futile cycles. This in turn causes cachexia by maintaining the organism in constant negative energy balance. Mitochondria-to-nucleus stress signaling activates some of the genes implicated in tumor progression and tumor cell metastasis. Retrograde regulation also renders the cell more resistant to apoptosis. It is becoming clearer which genes control the retrograde response in human cells. Most probably, MYC is one of the transcription factors necessary for this response.