Dysregulation of Mitochondrial Life Cycle and NAD+ Metabolome in Friedreich’s Ataxia Cardiomyopathy


Effect of NMD in other Tissue

Poster Number: 216


Michael Huang, PhD, Shannon Chiang, PhD, Nady Braidy, PhD, Sanaz Maleki, Sean Lal, MD, PhD, Des Richardson


1. University of Sydney, 2. University of Sydney, 3. University of New South Wales, 4. University of Sydney, 5. University of Sydney, 6. University of Sydney

Background: The heart is exquisitely dependent on the mitochondrion for energy production and vital cellular functions. However, as a result of high redox activity, the mitochondrion is also a major site of oxidative stress. To manage energy demands and decrease oxidative stress, mitochondrial homeostasis is maintained by the dynamic and critical processes of mitochondrial biogenesis, mitochondrial network dynamics (fusion/fission), and mitochondrial clearance by mitophagy.

Friedreich’s ataxia (FA) is a mitochondrial disease that manifests a fatal dilated cardiomyopathy due to the deficiency of the mitochondrial protein, frataxin. Our previous studies identified defective mitochondrial iron metabolism and oxidative stress that contribute to FA cardiac pathology. However, how these factors alter mitochondrial homeostasis remains uncharacterized in the pathogenesis of FA cardiomyopathy.

Objective: To elucidate the contribution of the alterations in mitochondrial homeostasis in FA cardiomyopathy.

Results: Using the muscle creatine kinase conditional frataxin KO mouse, which is a well-established model of FA cardiomyopathy, we assessed alterations in mitochondrial ultrastructure, metabolomics and molecular markers of mitochondrial homeostasis. These were then examined in FA patient’s heart samples.

In the frataxin KO mice heart relative to wild-type littermates, we identified: (1) proliferation of mitochondria with abnormal cristae structure; (2) impaired NAD+ metabolism due to perturbations in Sirt1 and Pgc1α activity; (3) increased markers of mitochondrial biogenesis and dynamics (both fusion and fission); and (4) mitochondrial accumulation of Pink1/parkin with increased autophagic flux and mitophagy. Immunohistochemistry assessment of FA patient’s heart confirmed enhanced expression of markers involved in mitochondrial biogenesis, fusion/fission and autophagy.

Conclusion: These novel findings demonstrate that cardiac frataxin-deficiency results in significant changes to mitochondrial homeostasis, and offer the potential for the development of new FA treatments that target mitochondrial function.