Opening Pharmacological Avenues in Mitochondrial Dysfunction: From Mood Disorders to Perioperative Anesthetic Complications

Abstract

Mitochondria act as a central integrative hub for oxidative phosphorylation, calcium homeostasis and metabolic signaling, reflecting their evolutionary origin from an α-proteobacterial endosymbiont. Although nearly 90% of their ancestral genes have been transferred to the nuclear genome, their role extends far beyond energy production. Emerging evidence positions mitochondria as active modulators of stress responses, which we term the "Mito-Mood Hypothesis." This framework proposes that mitochondrial dynamics actively regulate gene expression and signaling, thereby shaping vulnerability to mood disorders such as depression, dysthymia, and seasonal affective disorder. Consistent with this view, patients with major depressive disorders show altered expression of nuclear-encoded mitochondrial genes, linking bioenergetics directly to psychiatric risk. We further discuss how oxidative phosphorylation (OXPHOS) modulates neurotransmitter cycles and how mitohormesis— adaptive responses to mild mitochondrial stress—can enhance resilience and cognition. Beyond psychiatry, mitochondrial vulnerability manifests in clinical settings: patients with mitochondrial diseases face elevated anesthetic risk, where agents such as propofol or volatile anesthetics may precipitate life-threatening metabolic crises. Collectively, these insights underscore mitochondria as central regulators of human health and highlight novel therapeutic opportunities bridging mood disorders and perioperative medicine.