Frataxin degrading peptidase: A multifunctional regulator of mitochondrial energy production and iron balance

Abstract

Frataxin is a conserved mitochondrial protein whose deficiency causes mitochondrial iron imbalance, energy deficit, and oxidative stress, leading to the progressive neurologic and cardiac disease Friedreich ataxia. We reported previously that the mature form of human frataxin is degraded to shorter products by an unknown protease, designated frataxin degrading peptidase (FDP). We hypothesized that FDP might represent a new mechanism to modulate mitochondrial iron balance via regulation of frataxin turnover. We have now purified FDP from different tissue sources. Interestingly, the enzyme corresponds to a known mitochondrial homodimeric oxidoreductase involved in energy metabolism and antioxidant defense. The presence of proteolytic activity has been confirmed with a recombinant form of the oxidoreductase produced in E. coli. The 3D structure of the enzyme suggests the presence of a Ser-His-Glu catalytic triad at the homodimer interface. Indeed, the proteolytic activity is stimulated by point mutations or other conditions that destabilize the homodimer, and is inactivated by certain serine protease inhibitors. Combining oxidoreductase and proteolytic functions in the same protein may be a mechanism to integrate changes in energy metabolism and redox status with mitochondrial iron balance. [Supported by the Muscular Dystrophy Association and a pre-doctoral fellowship from the American Heart Association (0415379Z)].