In summary, our findings provide strong evidence showing that [1] TFAM is critical for mtDNA replication/transcription in HNCs [2]; TFAM loss/overexpression is sufficient to modulate HNC malignancy via metabolic reprogramming towards a cancer favourable metabolic state and modulations of oncogenic effector Akt and ERK pathways; and [3] expression of TFAM and mtDNA encoded ETC genes could predict HNC progression in preclinical and clinical specimens prior to conventional treatments. Here, TFAM is linked to cancer.