Legend for graphical abstract: Human-IFNα mediates mitochondrial calcification of human skeletal muscle cells (RH30 cells) in an mtROS-dependent manner. (I)mitochondrial oxidative stress (mtROS) downstream to IFNα lead to mitochondrial accumulation of calcium phosphate complexes of hydroxyapatite, potentially via altering mitochondrial calcium influx mechanisms . MtROS scavenger, MitoTempo, can inhibit this IFNα-mediated mitochondrial calcification. Calcified mitochondria are destabilized resulting in the cytosolic leakage of mtDNA via VDAC channel leading to cGAS-STING pathway activation and interferon-stimulated gene (ISG) expression, creating an autocrine loop of calcification and inflammation. VDAC1 channel inhibitor, VBIT-4 can inhibit this calcified mitochondria-mediated ISG expression. (II) Mitochondrial components (mtDNA and mtNFPs) released from calcifying skeletal muscle cells into extracellular space can be markers of muscle damage. Further, extracellular mitochondria can also be substrates for anti-mitochondrial antibodies (AMAs) that have a potential to be predictive markers for calcinosis. (III) Damaged and calcified mitochondria in the extracellular space can also serve as nidi for mineralization, contributing to the calcification to skeletal muscle. Dotted line represents potential pathway as reported in literature [59].