Recombinant mitochondrial transcription factor A with N-terminal mitochondrial transduction domain increases respiration and mitochondrial gene expression

We developed a scalable procedure to produce human mitochondrial transcription factor A (TFAM) modified with an N-terminal protein transduction domain (PTD) and mitochondrial localization signal (MLS) that allow it to cross membranes and enter mitochondria through its “mitochondrial transduction domain” (MTD = PTD + MLS). Alexa488-labeled MTD–TFAM rapidly entered the mitochondrial compartment of cybrid cells carrying the G11778A LHON mutation. MTD–TFAM reversibly increased respiration and levels of respiratory proteins. In vivo treatment of mice with MTD–TFAM increased motor endurance and complex I-driven respiration in mitochondria from brain and skeletal muscle. MTD–TFAM increases mitochondrial bioenergetics and holds promise for treatment of mitochondrial diseases involving deficiencies of energy production.