POLRMT, the mitochondrial RNA polymerase, is crucial for the transcription of the mitochondrial genome. It plays an essential role in mitochondrial biogenesis, as it is responsible for synthesizing the RNA transcripts that encode key proteins involved in the electron transport chain (ETC), a vital pathway for energy production in cells [2]. Additionally, POLRMT is also essential for mammalian mitochondrial DNA replication, being indispensable for the maintenance of human mtDNA [7].

Mutations in POLRMT can cause neurological diseases. Patients with POLRMT variants present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; some may also display progressive external ophthalmoplegia. Functional studies show that patient fibroblasts have defective mitochondrial mRNA synthesis [1]. In cancer, POLRMT is overexpressed in various types such as colorectal, prostate, and lung adenocarcinoma. Inhibiting POLRMT using small-molecule inhibitors like IMT1 disrupts mitochondrial functions in cancer cells, leading to mitochondrial depolarization, oxidative damage, decreased ATP levels, and ultimately inhibiting cancer cell growth both in vitro and in vivo [3,4,5,6]. Genetic depletion of POLRMT in cancer cells also impairs mitochondrial functions and suppresses cell viability, proliferation, and migration [4].

In conclusion, POLRMT is essential for mitochondrial transcription and DNA replication. Studies using loss-of-function models, such as genetic depletion in cancer cells and the analysis of POLRMT-mutated patients, have revealed its significant role in neurological diseases and cancer. These findings provide potential therapeutic targets for treating related diseases by targeting POLRMT-mediated mitochondrial functions.