From single and static organelles within the cell, the image of mitochondria has evolved to a dynamic cellular network in constant communication with other organelles. Indeed, their social nature allows their potential as signal transducer organelles which exert multiple functions beyond energy production. Recently, mitochondrial regulation of the innate immune response has become into a new functionality which determines cellular health. Mitochondria serve as platforms for the recruitment of complexes that forward signals to the nucleus in response to infections, with the aim of triggering inflammatory signaling pathways that, in turn, promote adequate immune responses. On the other hand, mitochondria act as a source of damage-associated molecular patterns (DAMPs), which initiate sterile inflammatory responses upon different stimuli. The mitochondrial genome (mtDNA), owing to its resemblance to a bacterial genome, is considered a mitochondrial DAMP (mtDAMP). The presence of mtDNA outside the mitochondrial compartment, either in the cytoplasm, inside endosomes or in the extracellular media, serves as an initial signal of mitochondrial dysfunction. Chronic mitochondrial damage leads to a robust activation of the innate immunity, triggering the expression of pro-inflammatory cytokines and interferon-related genes, impacting tissue and systemic homeostasis and potentially driving disease. In this chapter, we review the intracellular innate immune response mechanisms that can recognize mtDNA upon mitochondrial dysfunction, engaging aberrant sterile inflammation. We connect the state-of-the-art knowledge to the emerging role of inflammation as a common marker of age-related and mitochondria-associated diseases.