Abstract
Reactive oxygen species (ROS) are assumed to be implicated in the pathogenesis of inborn mitochondrial diseases affecting oxidative phosphorylation (OXPHOS). In the current study, we characterized the effects of three small molecules with antioxidant properties (N-acetylcysteine, ascorbate, and resveratrol) on ROS production and several OXPHOS parameters (growth in glucose free medium, ATP production, mitochondrial content and membrane potential (MMP)), in primary fibroblasts derived from seven patients with different molecularly defined and undefined mitochondrial diseases. N-acetylcysteine appeared to be the most beneficial compound, reducing ROS while increasing growth and ATP production in some patients’ cells. Ascorbate showed a variable positive or negative effect on ROS, ATP production, and mitochondrial content, while incubation with resveratrol disclosed either no effect or detrimental effect on ATP production and MMP in some cells. The individual responses highlight the importance of investigating multiple parameters in addition to ROS to obtain a more balanced view of the overall effect on OXPHOS when evaluating antioxidant treatment options for mitochondrial diseases.
Highlights
Mitochondria are double-membrane-bound organelles with a separate genome, present in nucleated eukaryotic cells
Electrons derived from the Krebs cycle are transported along the mitochondrial respiratory chain (MRC) complexes I–IV, resulting in the formation of an electrochemical proton gradient across the mitochondrial inner membrane, which is subsequently utilized by complex V, adenosine triphosphate (ATP) synthase, to generate ATP [1]
The first group consists of two patients with combined respiratory chain deficiency caused by mutations in nuclear-encoded components of the mitochondrial translation system
Summary
Mitochondria are double-membrane-bound organelles with a separate genome, present in nucleated eukaryotic cells. They are involved in several cellular processes and functions, including the crucial generation of cellular energy in the form of adenosine triphosphate (ATP) by oxidative phosphorylation (OXPHOS). Electrons derived from the Krebs cycle are transported along the mitochondrial respiratory chain (MRC) complexes I–IV, resulting in the formation of an electrochemical proton gradient across the mitochondrial inner membrane, which is subsequently utilized by complex V, ATP synthase, to generate ATP [1]. The estimated prevalence of adult mitochondrial diseases is approximately 1:4300 [2], while the minimum birth prevalence of mitochondrial respiratory chain disorders is approximately 6.2:100,000 [3]
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