Mitochondrial dysfunction is a key factor in the pathophysiology of major depressive disorder (MDD) and treatment-resistant depression (TRD), connecting oxidative stress, neuroinflammation, and reduced neuroplasticity. Physical exercise induces specific mitochondrial changes linked to improvements in mental health. The aim of this paper was to examine emerging evidence regarding the effects of physical exercise on mitochondrial function and treatment-resistant depression, highlighting the clinical importance of the use of mitochondrial biomarkers to personalize exercise prescriptions for patients with depression, particularly those who cannot tolerate standard treatments. Physical exercise improves mitochondrial function, enhances biogenesis and neuroplasticity, and decreases oxidative stress and neuroinflammation. Essential signaling pathways, including brain-derived neurotrophic factor, AMP-activated protein kinase, active peroxisome proliferator-activated receptor-γ coactivator-1α, and Ca2+/calmodulin-dependent protein kinase, support these effects. Most studies have concentrated on the impact of low- and moderate-intensity aerobic exercise on general health. However, new evidence suggests that resistance exercise and high-intensity interval training also promote healthy mitochondrial adaptations, although the specific exercise intensity required to achieve this goal remains to be determined. There is strong evidence that exercise is an effective treatment for MDD, particularly for TRD, by promoting specific mitochondrial adaptations. However, key gaps remain in our understanding of the optimal exercise dose and which patient subgroups are most likely to benefit from it (Graphical Abstract).

Background: Physical exercise (PE) has emerged as a promising intervention for depressive disorder (DD), yet its efficacy and optimal implementation remain under investigation. Objective: To thoroughly assess the effectiveness of supervised PE as a conventional intervention for adults with DD. Methods: A comprehensive literature search was conducted across PubMed/MEDLINE, EBSCOhost, Ovid, Web of Science, and Scopus. Randomized controlled trials (RCTs) published between 2010–2025 involving adults with DD without other comorbidities under supervised exercise interventions were selected. Methodological rigor was ensured through two independent reviewers and adherence to PRISMA 2020 guidelines. The influence of moderating variables [total work performed (workload) and the instrument used to evaluate DD (instrument)] was analyzed using meta-regression. The pooled effect size was estimated using both frequentist and Bayesian meta-analyses. Results: From 15,542 screened records, 20 RCTs were selected. Workload and instrument account for 60% and 15% of the variance in the effect size, respectively. Both frequentist and Bayesian meta-analyses showed that supervised PE reduces depressive symptoms (standardized mean difference = 0.82; 95% CI: 0.54–1.11; I² = 76%, and 0.61; 95% CI: −0.06–0.95; I² = 51, respectively). Conclusions: PE could be a valuable complementary intervention to reduce depressive symptoms in adults with depression. PROSPERO (CRD420251121919).

Glucose transporter type 4 (GLUT4), encoded by the SLC2A4 gene, is the final effector of insulin-stimulated glucose uptake in insulin-sensitive tissues: skeletal muscle, adipose tissue, and cardiac muscle. Its dynamic localization, retained intracellularly under basal conditions and extensively translocated to the plasma membrane upon stimulation, makes it a master regulator of glycemic homeostasis. While the canonical insulin pathway (PI3K/Akt/TBC1D4) is the most potent and specific mechanism in the postprandial state, its dysfunction is centrally associated with insulin resistance and type 2 diabetes mellitus (T2DM). Crucially, robust alternative signaling networks function completely independently of insulin to regulate GLUT4 synthesis and translocation. Prominent among these are contraction-mediated pathways in skeletal muscle, which employ calcium signaling (via CaMKII), mechanical/metabolic stress sensors (via p38 MAPK γ/δ), and AMP-activated protein kinase (AMPK). This review critically integrates current knowledge, linking the molecular architecture and post-translational modifications of GLUT4 to the complex, tissue-specific signaling networks that govern its vesicular trafficking. We emphasize the hierarchy, redundancy, and interdependence of these pathways, highlighting differences between acute translocation and chronic transcriptional adaptations. Finally, we discuss how deciphering insulin-independent mechanisms offers promising therapeutic opportunities, particularly in identifying pharmacological targets that mimic the metabolic benefits of physical exercise.

Glucose transporter type 4 (GLUT4), encoded by the SLC2A4 gene, is the final effector of insulin-stimulated glucose uptake in insulin-sensitive tissues: skeletal muscle, adipose tissue, and cardiac muscle. Its dynamic localization, retained intracellularly under basal conditions and massively translocated to the plasma membrane upon stimulation, makes it a master regulator of glycemic homeostasis. While the canonical insulin pathway (PI3K/Akt/TBC1D4) is the most potent and specific mechanism, its dysfunction is associated with insulin resistance and type 2 diabetes. Crucially, there are robust signaling pathways that are completely independent of insulin and regulate GLUT4 synthesis and translocation. Among these, those activated by muscle contraction are prominent, employing calcium signals (via CaMKII), mechanical/metabolic stress (via p38 MAPK γ/δ), and AMP-activated protein kinase (AMPK) activation. This review critically and comprehensively integrates current knowledge, from the molecular architecture of GLUT4 and its facilitated transport mechanism to the complex signaling networks converging on its regulation. The hierarchy, redundancy, and interdependence of these pathways are emphasized. It discusses how understanding insulin-independent mechanisms offers promising therapeutic opportunities for metabolic diseases, particularly for mimicking the benefits of exercise. Finally, future research directions are proposed to translate this molecular knowledge into novel clinical interventions.

Background: Physical exercise has emerged as a promising intervention for depressive disorder, yet its efficacy and optimal implementation remain under investigation. Ob-jective: To thoroughly assess the effectiveness of structured physical exercise as a con-ventional treatment for adults with depressive disorder. Methods: Adhering to PRISMA 2020 guidelines, a comprehensive literature search was conducted across PubMed/MEDLINE and institutional multi-databases. Peer-reviewed randomized controlled trials (RCTs) published between 2010 and 2025, studying adults diagnosed with depressive disorder under supervised exercise interventions, were se-lected. Methodological rigor was ensured through two independent reviewers. The in-fluence of moderating variables (workload and the instrument used to evaluate depres-sive disorder: instrument) was analyzed using meta-regression, and the pooled effect size was estimated using both frequentist and Bayesian meta-analyses. Results: From 15,542 screened records, 20 RCTs met the inclusion criteria. Workload accounts for 60% of the variance in the effect size, and instrument accounts the 15%. Supervised physical exercise significantly reduced depressive symptoms (standardized mean difference = 0.80; 95% CI: 0.57–1.03; I² = 59%). Robust Bayesian meta-analysis confirmed the consistency of these findings. Conclusion: Physical exercise serves as a valuable complement to traditional therapies for adults diagnosed with depressive disorder, resulting in clinically significant reductions in depressive symptoms.