Telomere dysfunction, which leads to p53-mediated cellular growth arrest, senescence, and apoptosis, is associated with progressive atrophy and functional decline in high-turnover tissues. However, its broader adverse impact across many tissues, including quiescent systems, has not been fully understood. Transcriptomic network analyses revealed that telomere dysfunction represses the peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β) and their downstream network in mice lacking either telomerase reverse transcriptase or telomerase RNA component genes. This repression is linked to impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species (ROS). In telomere dysfunctional mice, enforced *Tert* or *PGC-1α* expression, or germline deletion of *p53* substantially restores PGC network expression, mitochondrial respiration, cardiac function, and gluconeogenesis. The study demonstrates that telomere dysfunction activates p53, which binds and represses *PGC-1α* and *PGC-1β* promoters, forming a direct link between telomere and mitochondrial biology. This telomere-p53-PGC axis is proposed to contribute to organ and metabolic failure and diminishing organismal fitness in the context of telomere dysfunction.Telomere dysfunction, which leads to p53-mediated cellular growth arrest, senescence, and apoptosis, is associated with progressive atrophy and functional decline in high-turnover tissues. However, its broader adverse impact across many tissues, including quiescent systems, has not been fully understood. Transcriptomic network analyses revealed that telomere dysfunction represses the peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β) and their downstream network in mice lacking either telomerase reverse transcriptase or telomerase RNA component genes. This repression is linked to impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species (ROS). In telomere dysfunctional mice, enforced *Tert* or *PGC-1α* expression, or germline deletion of *p53* substantially restores PGC network expression, mitochondrial respiration, cardiac function, and gluconeogenesis. The study demonstrates that telomere dysfunction activates p53, which binds and represses *PGC-1α* and *PGC-1β* promoters, forming a direct link between telomere and mitochondrial biology. This telomere-p53-PGC axis is proposed to contribute to organ and metabolic failure and diminishing organismal fitness in the context of telomere dysfunction.