Mitochondrial Respiratory Function in Peripheral Blood Cells from Huntington's Disease Patients

Abstract

Background: Patients with Huntington's disease display symptoms from both the central nervous system and peripheral tissues. Mitochondrial dysfunction has been implicated as part of the pathogenesis of the disease and has been reported in brain tissue and extracerebral tissues, such as muscle and blood cells, but the results are inconsistent. Therefore, the authors performed a refined evaluation of mitochondrial function in 2 types of peripheral blood cells from 14 patients with Huntington's disease and 21 control subjects. Several hypotheses were predefined, including impaired mitochondrial complex II function (primary), complex I function (secondary), and maximum oxidative phosphorylation capacity (secondary) in patient cells. Methods: High-resolution respirometry was applied to viable platelets and mononuclear cells. Data were normalized to cell counts, citrate synthase activity, and mitochondrial DNA copy numbers. Results: Normalized to citrate synthase activity, platelets from patients with Huntington's disease displayed respiratory dysfunction linked to complex I, complex II, and lower maximum oxidative phosphorylation capacity. No difference was seen in mononuclear cells or when platelet data were normalized to cell counts or mitochondrial DNA. The ratio of complex I respiration through maximum oxidative phosphorylation was significantly decreased in patients compared with controls. The corresponding ratio for complex II was unaffected. Conclusions:The data indicate decreased function of mitochondrial complex I in peripheral blood cells from patients with Huntington's disease, although this could not be uniformly confirmed. The results do not confirm a systemic complex II dysfunction and do not currently support the use of mitochondrial function in blood cells as a biomarker for the disease.Huntington's disease (HD) is an autosomal-dominant, progressive, neurodegenerative disease with a phenotype dominated by characteristic chorea, cognitive decline, and psychiatric symptoms. HD is caused by a cytosine-adenine-guanine (CAG) repeat expansion in the huntingtin (HTT) gene, resulting in contiguous glutamine residues and subsequent gain of function in the translated protein.

Expression of Human Mutant Huntingtin Protein in Drosophila Hemocytes Impairs Immune Responses

“…The phagocytic capacity of immune cells has been associated with mitochondrial activity (28–30); mHTT has been shown to cause impairment of energy metabolism and mitochondrial dysfunction in human peripheral blood cells (31). To test whether mHTT can also impair the energy metabolism of Drosophila immune cells, we measured the ATP levels in S2 lineages after mHTT induction.…”

Integrated mitochondrial function and cancer-related fatigue in men with prostate cancer undergoing radiation therapy

“…Additionally, maximal oxidative capacity, uncoupled oxidation, starting at complex II was significantly decreased (↓22.9%) in mononuclear cell mitochondria at day 21 of XRT compared to that at day 0 before XRT. Using peripheral blood mononuclear cells, other investigators have reported decreased mitochondrial OXPHOS complex I and II-linked oxidation rates associated with the symptom of depression and fatigue in patients with Table 2 integrated mitochondrial function in peripheral blood mononuclear cells from prostate cancer patients undergoing radiation therapy (n=15) major depression, 39 in patients with Huntington disease, 40,41 and in pediatric septic shock. 42 These studies did not evaluate the OXPHOS-complex III-linked oxidation rate in human peripheral blood mononuclear cell mitochondria.…”

The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington’s disease

“…This could make a significant difference in the interpretation. Indeed, in living patients, normalizations for cell number changed the interpretation of the raw data as to the significance of the complex I and II defects in blood cells of HD patients (Ehinger et al, 2016). These authors concluded that blood was not a reliable source to discern bioenergetic differences in patients.…”

“…For example, in peripheral blood cells from 14 HD patients and 21 control subjects, direct measurements with a respirometer resulted in detection of statistically robust deficiencies only in mitochondrial complex I (Ehinger et al, 2016). Mitochondrial spare respiratory capacity is a measure of the ability of mitochondria to generate energy beyond that required for sustaining the basic metabolic needs.…”