Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.
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