title: Mitophagy or how to control the Jekyll and Hyde embedded in mitochondrial metabolism: implications for melanoma progression and drug resistance.
abstract: Proteins and pathways that control cell fate are placed under intense scrutiny. The same tight regulation applies to essential organelles that can both sustain cell survival or promote self-degradation programs. Mitochondria are perhaps the prime example of cellular machineries with split functions (personalities). As a main source of ATP, mitochondria represent the main powerhouse of eukaryotic cells. However, mitochondrial respiration has the hidden complication of the production of potentially harmful reactive oxygen species (ROS). Moreover, mitochondria holds an armamentarium of stress-response factors, which depending on the context, may lead to pro-inflammatory signals, and to various forms of cell death, ranging from apoptosis to necrosis. A main clearance mechanism to eliminate superfluous, damaged or hyperactive mitochondria is selective mitophagy. Mitophagy, in fact, is emerging as a key quality-control mechanism in cancer cells. Specifically, malignant transformation has been found to induce marked changes in mitochondrial dynamics and structure. Moreover, a key hallmark of tumor progression is metabolic reprogramming, which further deregulates ROS content and renders cells more susceptible to mitochondrial perturbations. Despite its increasing relevance in cancer biology, the field of mitophagy remains virtually unexplored in melanoma. However, given unique antioxidant mechanisms in melanocytic cells (e.g., linked to melanin) and the idiosyncratic interplay between ROS and hypoxia (both mitophagy inducers) in melanoma, this tumor type represents an ideal scenario for physiological studies of mitochondrial turnover. This perspective summarizes proof of concept for in-depth basic and translational studies of mitophagy in melanoma. Particular emphasis is dedicated to new opportunities for gene discovery and drug design in this still aggressive disease.
authors.affiliation: Melanoma Laboratory, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre), Madrid, Spain. msoengas@cnio.es
authors.forename: María S
authors.initials: MS
authors.lastname: Soengas
mesh_terms: D000818:Animals; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D012878:Skin Neoplasms / Q000473:pathology*