Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.

Beyond their classical role as "cellular powerhouses", mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics-including fusion-fission balance, mitophagy-biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion-contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions.