Abstract <p>This review systematizes contemporary data on the signaling role of mitochondrial metabolites in regulating mitochondrial homeostasis, with an emphasis on their influence on cellular adaptation to stress factors, including age-related changes. Mitochondria function not only as energy sources but also as key sensors and regulators, mediating anterograde and retrograde signaling through metabolites such as citrate, succinate, lactate, and L-carnitine. Citrate and succinate participate in epigenetic modifications, including protein acetylation and succinylation, thereby influencing gene expression and metabolic adaptation, with potential applications in the therapy of oncological and age-associated diseases. Lactate, traditionally regarded as a product of anaerobic metabolism, acts as a signaling molecule that modulates receptor cascades (GPR81), histone lactylation, and oxidative phosphorylation in mitochondria. L-carnitine ensures metabolic flexibility by maintaining the acyl-CoA/CoA balance, removing toxic metabolites, and enhancing nitric oxide bioavailability, demonstrating its protective effects in models of hyperhomocysteinemia and NO deficiency. Understanding these mechanisms opens up prospects for the identification of biomarkers of mitochondrial dysfunction and the development of therapeutic strategies aimed at restoring homeostasis in the context of aging, metabolic disorders, and gerontological syndromes.</p>