Phenotype-Specific Mitochondrial Responses to Mediterranean Diet and Exercise in Elderly Obesity

<b>Background/Objectives:</b> While excessive body fat is commonly linked to metabolic disorders (metabolically unhealthy obesity, MUO), a subset of individuals remain metabolic healthy despite obesity (metabolically healthy obesity, MHO). This work aims to determine how these phenotypes influence responses to lifestyle modification (LSM) in older adults. <b>Methods:</b> A 12-month lifestyle modification (LSM) intervention based on the Mediterranean Diet (MedDiet) and regular physical activity (PA) was conducted in 43 older adults (70% women) classified according to World Health Organization (WHO) criteria as MHO (22 subjects) or MUO (21 subjects). Clinical, dietary, and PA parameters were assessed at baseline and follow-up. Peripheral blood mononuclear cells were analyzed for mitochondrial fusion (OPA1, MFN2), mitophagy (PINK1), biogenesis (TFAM), and the respiratory chain (COX IV) using Western blot and RT-qPCR techniques. <b>Results:</b> At baseline, MUO showed significant lower OPA1-L, MFN2, and TFAM along with MFN2 degradation products and PINK1 accumulation. After 12 months of LSM, MUO participants exhibited greater metabolic profile improvements, such as significantly reduced MFN2 degradation products and higher COX IV. Changes in mitochondrial proteins were associated with nutrient intake and PA and clinical parameters with phenotype-specific patterns. In MUO, protein and cholesterol intake improved MFN2 fusion (rho = 0.446, <i>p</i> = 0.043; rho = 0.581, <i>p</i> = 0.006), while carbohydrates were negatively associated with OPA1 in MHO (rho = -0.596, <i>p</i> = 0.025). PA was positively related to fusion proteins in both phenotypes. Clinically, significant improvements in BMI, waist circumference, and HDL were found in MUO but not in MHO. <b>Conclusions:</b> Older adults with obesity show phenotype-specific mitochondrial impairments that shape distinct responses to LSM, highlighting the relevance of tailoring LSM interventions by metabolic phenotype.