**4. Autophagy**

Autophagy is the process of cellular recycling that promotes energy efficiency through the generation of ATP and mediates damage control through the elimination of organelles and nonfunctional proteins, in regulating the degradation of cytosolic components by the liposomes [40]. Autophagy is the main catabolic pathway through which macromolecules and organelles of the eukaryotic cells are degraded and recycled. This pathway is activated under conditions of environmental stress and during the development of diverse pathologic situations. Autophagy plays an essential role in the cellular differentiation, development, and response to stress. It is activated during amino acid deprivation and is associated with neurodegenerative illnesses, cancer, pathogenic infections, and myopathies [41]. Autophagy can be induced by diverse causes: mitochondrial dysfunctions, infections of intracellular pathogens, and intrinsic cellular signals. Folded or damaged proteins, the organelles, and the intracellular pathogens are isolated by double membrane vesicles forming autophagosomes, which, on fusing with the lysosomes, convert into autolysosomes to be degraded [42]. Autophagy is an active process that plays the role of cleansing in maintaining the integrity of the intracellular organelles and proteins; however, autophagy is strongly induced by starvation, as in the case of cellular hypoxia, and is a key component in the adaptive response of the cells and organisms to the lack of nutrients, in order to promote cellular survival until the nutrients are made available once more [43]. Thirty-two different genes have been identified in relation to autophagy, obtained by genetic screening in yeasts. Many of these genes can be found in mold, plants, worms, flies, and in mammals, emphasizing, through phylogeny, the importance of the autophagy process in response to starvation [44]. Three types of autophagy that promote proteolytic degradation of the cytosolic components in lysosomes have been defined:

**a.** *Macroautophagy:* the cytoplasmic load is given to the lysosomes through a vesicle with a double-layered membrane called an autophagosome, which fuses with the lysosome to form the autolysosome. Macroautophagy is capable of engulfing large structures through selective and nonselective mechanisms.


The autophagy mechanism begins with an isolation membrane (phagophore), probably derived from the lipid bilayer originating in the endoplasmic reticulum (ER), and/or through the Golgi apparatus and endosomes [46]. The phagophore expands to engulf intracellular components, isolating protein aggregates, organelles and ribosomes, and forming an autophagosome with a double membrane. The autophagosome matures through fusion with the lysosome, promoting the degradation of the autophagosome content by acidic lysosome proteases. The lysosomal permeases and transporters export amino acids and by-products of degradation to the cytoplasm, where they can be reused for the construction of macromolecules and for metabolism [47]. Selective degradation of the mitochondria mediated by autophagy is called mitophagy [48]. It seems the absence of functional mitochondria produced by metabolic deregulation and autophagy obligates the muscle cells to gain energy without the participation of the Krebs cycle, in comparison to intact mitochondria. The mitochondrial degradation dependent on autophagy or mitophagy is an important process to maintain the critical integrity of the mitochondria and to limit the production of ROS [49]. The deregulation of autophagy and mitochondrial dysfunction could represent key aspects in the pathophysiology of FM [50]. The authors demonstrate that CoQ deficient fibroblasts exhibite increased levels of lysosomal markers (beta-galactosidase, cathepsin, LC3, and Lyso Tracker), and enhanced expression of autophagic genes at both transcriptional and translational levels, indicating the presence of autophagy [51]. CoQ10 deficiency apparently induces autophagy activation in mononuclear blood cells (BMCs) of FM patients by finding increased levels of acid vacuoles in BMCs identified by Lysotracker fluorescence and flow cytometry analysis. The authors suggest restoring mitochondrial functionality with CoQ10 supplementation as demonstrated in *in vitro* studies with decreased lysosomal activity following treatment with CoQ10 [52]. Autophagy is an attractive, strategic target for investigation of bodily fluids or muscle biopsies in patients who suffer FM (**Figure 2**).
