Mitochondrial hTERT rewires glucose metabolism to confer cancer chemoresistance by binding to MT-ND1

Abstract Resistance to chemotherapy represents a bottleneck in clinical cancer treatment and demands urgent solutions. Dysfunction of glucose metabolism including the Warburg effect is an outstanding hallmark of aberrant cancer metabolism which remarkably fosters chemoresistance. Targeting disordered mitochondrial metabolism have paved the road for enhancing chemosensitivity. Human telomerase reverse transcriptase (hTERT) is tightly associated with cancer initiation and progression. Notably, hTERT can unconventionally translocate from nucleus to mitochondria. However, the influence of mitochondrial hTERT on glucose metabolism and the subsequent contribution to chemoresistance remains largely elusive. Here, we uncovered that mitochondrial hTERT level is negatively with chemotherapy response in patients, and disclosed the undocumented role of mitochondrial hTERT in reprogramming cancer metabolism towards Warburg effect independent of RT activity which authentically promoted chemoresistance. Mitochondrial hTERT boosted Warburg effect and weakened oxidative phosphorylation (OXPHOS) specifically via suppressing Complex I activity.Interactome profiling by mass spectrometry revealed that mitochondrial hTERT physically interacted with Complex I core subunit MT-ND1 (ND1) through its matrix loop region to hinder Complex I functions. A novel TAT-Pep designed on the basis of their interacting region effectively abrogated the hTERT-ND1 interplay, which substantially rejuvenated Complex I activity and rewired cancer metabolism from Warburg effect towards OXPHOS thereby strengthening chemosensitivity in both resistant cancer lines and patient-derived xenograft (PDX) tumor models. Collectively,our study reveals the interaction between MT-ND1 and hTERT as an essential mechanism that underlies the rewiring of cellular glucose metabolism and chemoresistance. Targeting mitochondrial hTERT-governed adverse metabolic remodeling sheds light on the avenue towards better chemotherapeutics efficacy.