Mitochondrial Metabolism and FRDA Vulnerability
Abstract
Friedreich ataxia (FRDA) is a prevalent genetic disorder characterized by cardiomyopathy and progressive neurological disease and is associated with an increased incidence of diabetes mellitus. The genetic perturbation is a trinucleotide GAA expansion in the FRATAXIN (FXN) gene, which encodes a mitochondrial protein (also called FXN). Mitochondria are the main producers of cellular energy, and when they fail to work, cells are no longer able to function properly and will die. The precise function of FXN in mitochondria and why its loss leads to disease remain unclear, however, making it difficult to identify an effective target for therapeutic intervention. One very curious aspect of FRDA disease is that, although mitochondria are required in all cells in the body, some cells are much more affected by the loss of FXN protein than others. A very striking example of the cell-type-selective FRDA vulnerability can be seen in the peripheral somatosensory nervous system. This sensory system comprises three main classes of neurons, including neurons that cause us to feel pain when we are hurt (pain neurons), neurons that allow us to feel touch (touch neurons), as well as neurons that allow us to feel where our limbs are relative to the rest of the body (proprioceptor neurons). While touch and proprioceptive neurons are among the earliest and most severely affected in FRDA disease, pain neurons are largely unaffected in FRDA. We believe that by studying why some tissues are more vulnerable to the loss of FXN (heart, touch, and proprioceptor neurons) and what these tissues may have in common, we may better understand the role of FXN in causing FRDA. In our lab, we study differences in FRDA vulnerability between pain and touch sensory neurons using induced pluripotent stem cells (iPSCs). Pluripotent stem cells can be made to differentiate into all cell types in the body. For our studies, we developed methods to generate pain and touch neurons from iPSCs that were derived from cells from FRDA patients. FRDA iPSC cells in which the FXN mutation was corrected served as control cell lines. We also manipulated these FRDA and control iPSCs genetically, to mark the pain or touch neurons (after they differentiate) with a fluorescent protein (allowing us to visually identify the neurons). In our preliminary phenotypic analysis of these neurons, we obtained three major and exciting results. First, when differentiating FRDA and control iPSCs into pain or touch neurons, we found that their differential vulnerability is recapitulated in vitro: FRDA touch neurons exhibit reduced growth compared to control touch neurons, but we observed no difference between FRDA and control pain neurons. Second, we found a profound divergence in mitochondrial metabolism between these two sensory neurons: mitochondria from pain neurons mainly rely on the use of pyruvate as their fuel to sustain their main function (ATP production), while mitochondria from touch neurons – similar to cardiomyocytes – primarily use fatty acids (FAs) and/or amino acids (AAs). Third, mitochondrial metabolism in FRDA pain neurons is minimally affected, if at all, by the loss of FXN. In contrast, in FRDA touch neurons pyruvate use is unaltered, but the use of FAs or AAs as mitochondrial fuels is impaired. Based on these observations, our central hypothesis is that sensory neurons that rely on FAs as a mitochondrial fuel are disproportionally vulnerable to a loss of FXN compared to neurons that rely on pyruvate as their mitochondrial energy source. In this proposal, we will investigate this idea by (a) comparing the mitochondrial metabolic pathways between touch and pain neurons and by (b) defining the requirement of FXN in sensory neuron FA and pyruvate metabolism. Thus, these studies will delineate the metabolic consequences of FXN loss in the context of neuronal subtypes that rely on different energy substrates and may help identify commonalities in FRDA disease mechanisms in hear
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310092
Entities
People
- Joriene De Nooij
Organizations
- Columbia University
- United States Army