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. 2023 May 19;12(10):3560.
doi: 10.3390/jcm12103560.

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients

Cristina González-Mingot  1 , Francisco Javier Miana-Mena  2 , Pedro José Iñarrea  3 , Cristina Iñiguez  4 , José Luis Capablo  5 , Rosario Osta  2 , Anna Gil-Sánchez  1 , Luis Brieva  1 , Pilar Larrodé  4
Affiliations

Mitochondrial Aconitase Enzymatic Activity: A Potential Long-Term Survival Biomarker in the Blood of ALS Patients

Cristina González-Mingot et al. J Clin Med. .

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. 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. 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 propose the feasibility of using them as possible valid biomarkers to quantify the progression of the disease and as a predictor of individual prognosis in ALS.

Methods: We measured the Aco2 enzymatic activity in the 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 onset (p < 0.05) and in those with predominantly upper motor neuron signs.

Conclusions: Aco2 activity seems to be an independent factor that could be used in the long-term survival prognosis of ALS. Our findings suggest that blood Aco2 could be a leading candidate for use as a biomarker to improve prognosis. More studies are needed to confirm these results.

Keywords: ALS; aconitase; biomarker; enzymatic activity; mitochondrial antioxidant activity.

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Conflict of interest statement

The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1
Figure 1
Mean Aco2 activity in ALS patients and controls. The value of Aco2 activity in the ALS patients was 257.65 ± 111.1 mU/mg, whereas in the controls, it was 375.41 ± 166 mU/mg (p < 0.05). ALS: Amyothophic lateral sclerosis. Aco2: Aconitase 2.
Figure 2
Figure 2
Aco2 activity in subjects with survival periods of ≥36 months was 328.25 ± 90 mU/mg as opposed to 22.28 ± 106.9 mU/mg in subjects with survival periods of <36 months (p < 0.05).
Figure 3
Figure 3
Aco2 activity levels were higher in patients with early onset than in the late group (p < 0.01).
Figure 4
Figure 4
Aco2 activity levels were higher in patients with UMN than in those with predominantly LMN involvement (Aco2 activity of 368.83 ± 47.4 mU/mg versus 227.42 ± 92.9 mU/mg (p < 0.05)). UMN: Upper motor neuron, LMN: Lower motor neuron, MN: Motor neuron.
Figure 5
Figure 5
The ROC (receiver operating characteristic) curve is a graphical representation of the performance of a binary classifier that predicts the probability of a positive outcome. The area under the curve (AUC) represents the overall performance of the classifier, with a higher AUC indicating better performance. An AUC of 1.0 indicates perfect classification, while an AUC of 0.5 (red line) indicates random guessing. In our case, Aco2 activity could be considered a good predictor of long-term survival because its AUC value was 0.75 (p = 0.03).
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