Considering Mitophagy and Cancer

Mitophagy is the process by which damaged or excess mitochondria in cells are destroyed, their parts recycled. Mitochondria, and in particular the level of damage in mitochondria, are important in aging. For most things that are important in aging, there is also a fair amount of evidence suggesting relevance to cancer, and mitochondria are no exception. Researchers here consider some of the known links between the modulation of mitophagy and the development of cancer, and taken as a whole the evidence suggests anything but a simple relationship. Depending on the particular context, when it comes to cancer it can be argued that either less mitophagy or more mitophagy is a bad thing. This is not the case for aging, in which greater mitophagy should always be beneficial, to the extent that it maintains lower levels of mitochondrial damage and the harms that result from that damage.

Macroautophagy, hereafter referred to as autophagy, is a highly conserved degradation process targeting large and possibly toxic structures in the cell. Mitochondria-selective autophagy (mitophagy) plays a pivotal role in the maintenance of mitochondrial homeostasis, regulating the size and quality of the mitochondrial population. In addition, mitophagy eliminates damaged mitochondria under diverse stress conditions. Healthy mitochondria are also removed when attenuation of mitochondrial function is required upon hypoxia, caloric restriction, or during certain developmental processes. Mitochondrial surveillance and quality control mechanisms, including mitophagy, decline with age and in several pathologies, causing progressive deterioration of mitochondrial function. Deregulation of mitophagy is closely linked to cancer development and progression. Thus, elucidation of the mechanisms governing mitophagy holds promise for novel anticancer interventions.

In C. elegans, inhibition of mitophagy increases mitochondrial mass, uncouples respiration from ATP production, enhances mitochondrial ROS production, and increases cytoplasmic calcium levels. These phenotypes are commonly observed in aged animals, and across large evolutionary distance. Increased ROS contribute to carcinogenesis by causing DNA damage and triggering aberrant alterations in gene expression. Therefore, in addition to the manifestation of pro-aging phenotypes, impairment of mitophagy potentially facilitates tumorigenesis. Yet cancer cells within several types of solid tumors induce autophagy and mitophagy to adjust to their microenvironment of limited nutrient and oxygen availability. In the largely hypoxic solid tumor environment, energy production shifts from oxidative phosphorylation to glycolysis, leading to increased glucose uptake and reduced oxygen consumption, a phenomenon known as the Warburg effect. Mitophagy induction has thus been proposed to be part of a hypoxia adaptation response that promotes cancer cell survival.

Notably, we found that DCT-1 upregulation under mitophagy-inducing conditions is mediated by SKN-1, the nematode homolog of mammalian Nrf2, a transcription factor that becomes activated upon oxidative stress to preserve mitochondrial homeostasis. SKN-1 also stimulates the expression of core mitochondrial components, promoting the assembly of fresh mitochondria. Our findings reveal a new layer of mitophagy regulation, which interfaces with mitochondrial biogenesis resulting in rejuvenation of the cell's mitochondrial pool. These observations highlight SKN-1/NRF2 as a new anticancer target whose activation could induce both mitophagy and mitochondrial biogenesis. This dual coordinating role may shield mitochondrial metabolism from oncogenic transformation by opposing the Warburg effect to increase healthspan. Decreased insulin signaling is an evolutionarily conserved molecular pathway that promotes longevity. We have shown that mitophagy is a significant contributor to lifespan extension under low insulin conditions. Indeed, inhibition of mitophagy shortens the lifespan of long-lived animals carrying lesions in daf-2, the gene encoding the sole insulin/IGF-1 receptor homolog in C. elegans. SKN-1 and DAF-16 underlie mitophagy induction under low insulin signaling conditions.

In summary, mitophagy is emerging as a nexus of cellular and organismal physiology. Several mitophagy promoting conditions engage distinct transcription factors that impinge on cancer-associated processes. The extent of mitophagy induction is critical for the onset and progression of carcinogenesis. Impairment of mitophagy in healthy tissues can promote tumor formation and mobility of cancer cells, whereas mitophagy induction in hypoxic solid tumors promotes adaptation and tumor cell survival. Coordination of mitochondrial biogenesis and removal could provide a new pathway to circumvent the adverse effects of mitophagy in this context. Further dissection of this pathway could unravel new potential anticancer interventions targeting tumorigenesis by promoting mitochondrial rejuvenation.



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