The importance of mitochondria and mitochondrial calcium signaling in health and disease: an updated outlook on inflammation

Mitochondria are central regulators of cellular bioenergetics, calcium homeostasis and apoptosis. Beyond these classical roles, emerging evidence highlights their pivotal involvement in inflammation and related disease progression. Under physiological conditions, mitochondria sustain metabolism and signaling; however, when dysfunctional, they can release mitochondrial damage-associated molecular patterns, such as mitochondrial DNA, reactive oxygen species, cardiolipin and ATP, into the intra- or extracellular environment. The release of these mitochondrial components activates innate immune receptors and inflammasomes, thereby initiating or sustaining inflammatory cascades implicated in aging and a broad range of diseases, including cancer and neurodegenerative, cardiovascular, gastrointestinal and respiratory disorders. Mitochondrial calcium signaling plays a crucial role in energy production and metabolic adaptation; yet when dysregulated, it promotes ROS generation, membrane permeabilization and cell death, all of which further amplify inflammation. Structural and functional mitochondrial messengers, including mtDNA fragments and mitochondria-derived vesicles, also contribute to intercellular communication, enhancing immune activation or driving chronic inflammation depending on their context. Therapeutically, mitochondria are emerging as promising targets to counteract inflammation. Investigational strategies include mitochondrial transplantation, engineered mitovesicles, pharmacological modulators of Ca2 + flux, antioxidants, and agents that restore mitochondrial biogenesis and metabolism. By reestablishing mitochondrial integrity, these interventions aim to reduce inflammatory signaling, restore cellular homeostasis, and slow disease progression. This review underscores mitochondria as both initiators and regulators of inflammatory processes across multiple diseases, highlighting their dual role as drivers of pathology and as promising therapeutic targets. A deeper understanding of mitochondrial signaling, mitochondrial messengers, and inter-organelle communication will be essential for developing effective mitochondria-based therapies to mitigate inflammation and improve patient outcomes.