Skeletal muscle remodeling and regeneration are achieved through the fine regulation of converging pathways that ultimately balance muscle protein synthesis and degradation [1].

Mitochondria are essential to support muscle contractile activity during daily tasks [2]. In addition, mitochondrial remodeling, via mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, is recognized as a relevant contributor to the regulation of myogenesis and skeletal muscle regeneration [2]. All of these processes are implicated in guaranteeing mitochondrial quality, the preservation of which is also instrumental to skeletal myocyte repair and myogenesis. A dysregulation in any of these pathways compromises mitochondrial quality and may potentially lead to impaired myogenesis, defective muscle regeneration, and ultimately loss of muscle function [2].

Among mitochondrial quality control (MQC) processes, mitophagy has gained special attention as for its implication in the clearance of dysfunctional organelles through crosstalk with other degradative cell’s compartments, such as the endo-lysosomal system [3]. Along the latter signaling route, additional pathways of mitochondrial disposal have been identified that may eventually signal at the systemic level. This communication occurs via inclusion of mitochondrial components within vesicles that are released at the extracellular level and are specifically referred to as mitochondrial-derived vesicles (MDVs) [4].

Here, we discuss MDV generation as a mitophagy complementing route to preserve mitochondrial homeostasis in skeletal myocytes. We also provide an overview on the mechanisms involved in mitochondrial DNA (mtDNA) release in the setting of failing quality control systems, and their possible implication in immune signaling during muscle remodeling and adaptation.