Mitochondrial pathophysiology in Friedreich's ataxia

Abstract

Neurological examination indicates that Friedreich's ataxia corresponds to a mixed sensory and cerebellar ataxia, which affects the proprioceptive pathways. Neuropathology and pathophysiology of Friedreich's ataxia involves the peripheral sensory nerves, dorsal root ganglia, posterior columns, the spinocerebellar, and corticospinal tracts of the spinal cord, gracile and cuneate nuclei, dorsal nuclei of Clarke, and the dentate nucleus. Involvement of the myocardium and pancreatic islets of Langerhans indicates that it is also a systemic disease. The pathophysiology of the disease is the consequence of frataxin deficiency in the mitochondria and cells. Some of the biological consequences are currently recognized such as the effects on iron-sulfur cluster biogenesis or the oxidative status, but others deserve to be studied in depth. Among physiological aspects of mitochondria that have been associated with neurodegeneration and may be interesting to investigate in Friedreich's ataxia we can include mitochondrial dynamics and movement, communication with other organelles especially the endoplasmic reticulum, calcium homeostasis, apoptosis, and mitochondrial biogenesis and quality control. Changes in the mitochondrial physiology and transport in peripheral and central axons and mitochondrial metabolic functions such as bioenergetics and energy delivery in the synapses are also relevant functions to be considered. Thus, to understand the general pathophysiology of the disease and fundamental pathogenic mechanisms such as dying-back axonopathy, and determine molecular, cellular and tissue therapeutic targets, we need to discover the effect of frataxin depletion on mitochondrial properties and on specific cell susceptibility in the nervous system and other affected organs.

The role of frataxin in doxorubicin-mediated cardiac hypertrophy

“…These deficits are characterized by reduced oxidative capacity due to depleted FXN levels and hence display impairment in Fe-S cluster enzyme activities, diminished respiratory capacity, and reduced ATP levels (12,14). Similar events were observed in our DOX-treated cardiomyoblasts, which displayed severe reduction in the activities of ISC containing enzymes, NADH and aconitase, as well as oxygen consumption levels and ATP production.…”

“…FRDA models are known to display severe mitochondrial energy deficits (14,26). These deficits are characterized by reduced oxidative capacity due to depleted FXN levels and hence display impairment in Fe-S cluster enzyme activities, diminished respiratory capacity, and reduced ATP levels (12,14).…”

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

“…The negative effects of Fxn deficiency, specifically in the mitochondria, are related to the cell's redox status (Lefevre et al, 2012;Gonzalez-Cabo & Palau, 2013). Therefore, 96 h after transduction with the SCR or the shRNA37 lentivirus we evaluated both mitochondrial morphology and superoxide generation in HAs labeled with MitoTracker red and MitoSOX red probes.…”

Oxidative Modulation of K+ Channels in the Central Nervous System in Neurodegenerative Diseases and Aging

“…There is a vast literature describing specific details of mitochondrial defects associated with each of these major diseases, and it is apparent that most if not all aspects of mitochondrial function, movement and turnover can be disrupted; several excellent review articles provide extensive detailed accounts of mitochondrial dysfunction in neurodegenerative diseases (25,42,51,71,80,88,112,189). Here, the focus on mitochondria is purely as a source of ROS, which is clearly elevated in all of these diseases.…”