Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Abstract

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.

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

“…PGC‐1a, the master regulator of mitochondria biogenesis, also plays a role in FRDA development. Lin et al demonstrated that in diseased FRDA mouse models, both PGC‐1a and its downstream effectors are significantly reduced compared to healthy controls. This impairment occurred early in the mitochondrial biogenesis pathway and is considered a potential therapeutic target for FRDA treatment.…”

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

“…According to this hypothesis, "young" and immature iPSC-derived neurons could provide information on early disease mechanisms. Our FRDA CNS neurons do not show any phenotypical deficit like the ones described for other FRDA cell types or animal models (27,50,51,53,(69)(70)(71)(72)(73)(74)(75)(76)(77)(78). Complex I, Complex III and aconitase activity were all similar to unaffected neurons and so were oxygen consumption, spare respiratory capacity, ATP production, reactive oxygen species formation and mitochondrial membrane potential (MMP, data not shown), while others have shown reduction in MMP (79), increased oxidative stress and decreased levels of Fe-S cluster-and lipoic acid-containing proteins (80) in iPSC-derived FRDA neurons compared to controls.…”

“…These changes are small but involve multiple aspects of cell metabolism. FRDA neurons show a decrease in mitochondrial protein transcript levels, such as components of the ATP synthase complex and of complex I (black module), all of which have been described in FRDA (23,27,(49)(50)(51). We observe consistent changes in ECM organization, focal adhesion and related signaling (brown and magenta modules and SNs), possibly linked to cytoskeletal abnormalities that have been reported in FRDA cells (52)(53)(54).…”

Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich's Ataxia Mouse Model

“…These PDE inhibitors provide mitochondrial bioenergetics promotion, antioxidant effects, and neuroprotective and neuroregenerative actions. Because decreased mitochondrial biogenesis has been demonstrated in mononuclear cells from peripheral blood of FRDA patients, in FRDA cells and mouse models [64,65], as well as decreased mitochondrial potential membrane and increased ROS production in cerebellar neurons from YG8R mice [46] among other neuronal models [14,27], it would seem that PDE inhibitors may display potential therapeutic benefits in FRDA. Resveratrol, a nonselective PDE inhibitor, increases FXN expression in cellular and mouse models of FRDA and has clinical benefits in FRDA patients by improving oxidative stress and clinical outcomes [50].…”