POLG and Mitochondrial encephalopathy: Concurrently, decreased SIRT1 signaling and increased UCP2 signaling contribute to neuronal senescence.398 The combination of mitochondrial dysfunction and senescence leads to neuron loss in POLG-related disorders.398 Astrocytes, which play a pivotal role in supporting neurons,399 also suffer from dysfunction due to mtDNA defects, contributing to the development of mitochondrial encephalopathy.