Mitochondrial Aconitase enzymatic activity: a potential long survival biomarker in the blood of ALS patients

Abstract Background: Amyotrophic Lateral Sclerosis (ALS) is a multisystemic, progressive, neurodegenerative disorder. Despite it being generally fatal within a period of 2–4 years, it is highly heterogeneous; as a result, survival periods may vary greatly among individual patients. In the absence of a single reliable test for ALS, Biomarkers can serve as tools for diagnosis, prognosis, indicators of therapeutic response, and future therapeutics. Free radical-dependent mitochondrial damage is believed to play a crucial role in neurodegeneration in ALS. Mitochondrial Aconitase, which is also known as Aconitase 2 (Aco2), is a key Krebs cycle enzyme and is involved in the regulation of cellular metabolism and iron homeostasis. Aco2 is very sensitive to oxidative inactivation and can aggregate and accumulate in the mitochondrial matrix, causing mitochondrial dysfunction. A loss of Aco2 activity may therefore reflect increased levels of mitochondrial dysfunction due to oxidative damage and could be relevant to ALS pathogenesis. The aim of our study was to confirm changes in Mitochondrial Aconitase activity in peripheral blood and to determine whether such changes are dependent on, or independent of, the patient's condition and to explore the feasibility of using them as valid biomarkers for quantifying disease progression and as an individual prognosispredictor in ALS. Methods: We measured Aco2 enzymatic activity in platelets of blood samples taken from 22 controls and 26 ALS patients at different stages of disease development. We then correlated antioxidant activity with clinical and prognostic variables. Results: Aco2 activity was significantly lower in the 26 ALS patients than in the 22 controls (p<0.05). Patients with higher levels of Aco2 activity survived longer than those with lower levels (p<0.05). Aco2 activity was also higher in patients with earlier onsets (p< 0.05) and in those with predominantly upper motor neuron signs. Conclusions: Aco2 activity is an independent factor that can be used in the long-survival prognosis of ALS. Our findings suggest that blood Aco2 is a leading candidate for use as a biomarker for improving prognosis. It could facilitate participant stratification in future ALS therapeutic trials and offer additional potential for therapeutic targeting.