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The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function.
Int J Mol Sci. 2020 Nov 30; 21(23)IJ

Abstract

Methylmalonic acidemia is an inborn metabolic disease of propionate catabolism, biochemically characterized by accumulation of methylmalonic acid (MMA) to millimolar concentrations in tissues and body fluids. However, MMA's role in the pathophysiology of the disorder and its status as a "toxic intermediate" is unclear, despite evidence for its ability to compromise antioxidant defenses and induce mitochondrial dysfunction. Coenzyme Q10 (CoQ10) is a prominent electron carrier in the mitochondrial respiratory chain (MRC) and a lipid-soluble antioxidant which has been reported to be deficient in patient-derived fibroblasts and renal tissue from an animal model of the disease. However, at present, it is uncertain which factors are responsible for inducing this CoQ10 deficiency or the effect of this deficit in CoQ10 status on mitochondrial function. Therefore, in this study, we investigated the potential of MMA, the principal metabolite that accumulates in methylmalonic acidemia, to induce a cellular CoQ10 deficiency. In view of the severe neurological presentation of patients with this condition, human neuroblastoma SH-SY5Y cells were used as a neuronal cell model for this investigation. Following treatment with pathological concentrations of MMA (>0.5 mM), we found a significant (p = 0.0087) ~75% reduction in neuronal cell CoQ10 status together with a significant (p = 0.0099) decrease in MRC complex II-III activity at higher concentrations (>2 mM). The deficits in neuronal CoQ10 status and MRC complex II-III activity were associated with a loss of cell viability. However, no significant impairment of mitochondrial membrane potential (ΔΨm) was detectable. These findings indicate the potential of pathological concentrations of MMA to induce a neuronal cell CoQ10 deficiency with an associated loss of MRC complex II-III activity. However, in the absence of an impairment of ΔΨm, the contribution this potential deficit in cellular CoQ10 status makes towards the disease pathophysiology methylmalonic acidemia has yet to be fully elucidated.

Authors+Show Affiliations

Department of Biochemistry, University of Warwick, Coventry CV4 7AL, UK.School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.Department of Clinical Biochemistry, The Royal Liverpool University Hospital, Royal Liverpool and Broadgreen NHS Trust, Prescot Street, Liverpool L7 8XP, UK.School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33266298

Citation

Proctor, Emma C., et al. "The Effect of Methylmalonic Acid Treatment On Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function." International Journal of Molecular Sciences, vol. 21, no. 23, 2020.
Proctor EC, Turton N, Boan EJ, et al. The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function. Int J Mol Sci. 2020;21(23).
Proctor, E. C., Turton, N., Boan, E. J., Bennett, E., Philips, S., Heaton, R. A., & Hargreaves, I. P. (2020). The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function. International Journal of Molecular Sciences, 21(23). https://doi.org/10.3390/ijms21239137
Proctor EC, et al. The Effect of Methylmalonic Acid Treatment On Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function. Int J Mol Sci. 2020 Nov 30;21(23) PubMed PMID: 33266298.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Effect of Methylmalonic Acid Treatment on Human Neuronal Cell Coenzyme Q10 Status and Mitochondrial Function. AU - Proctor,Emma C, AU - Turton,Nadia, AU - Boan,Elle Jo, AU - Bennett,Emily, AU - Philips,Suzannah, AU - Heaton,Robert A, AU - Hargreaves,Iain P, Y1 - 2020/11/30/ PY - 2020/10/30/received PY - 2020/11/26/revised PY - 2020/11/27/accepted PY - 2020/12/3/entrez PY - 2020/12/4/pubmed PY - 2021/3/9/medline KW - coenzyme Q10 KW - methylmalonic acidemia KW - mitochondrial dysfunction KW - mitochondrial membrane potential KW - mitochondrial respiratory chain JF - International journal of molecular sciences JO - Int J Mol Sci VL - 21 IS - 23 N2 - Methylmalonic acidemia is an inborn metabolic disease of propionate catabolism, biochemically characterized by accumulation of methylmalonic acid (MMA) to millimolar concentrations in tissues and body fluids. However, MMA's role in the pathophysiology of the disorder and its status as a "toxic intermediate" is unclear, despite evidence for its ability to compromise antioxidant defenses and induce mitochondrial dysfunction. Coenzyme Q10 (CoQ10) is a prominent electron carrier in the mitochondrial respiratory chain (MRC) and a lipid-soluble antioxidant which has been reported to be deficient in patient-derived fibroblasts and renal tissue from an animal model of the disease. However, at present, it is uncertain which factors are responsible for inducing this CoQ10 deficiency or the effect of this deficit in CoQ10 status on mitochondrial function. Therefore, in this study, we investigated the potential of MMA, the principal metabolite that accumulates in methylmalonic acidemia, to induce a cellular CoQ10 deficiency. In view of the severe neurological presentation of patients with this condition, human neuroblastoma SH-SY5Y cells were used as a neuronal cell model for this investigation. Following treatment with pathological concentrations of MMA (>0.5 mM), we found a significant (p = 0.0087) ~75% reduction in neuronal cell CoQ10 status together with a significant (p = 0.0099) decrease in MRC complex II-III activity at higher concentrations (>2 mM). The deficits in neuronal CoQ10 status and MRC complex II-III activity were associated with a loss of cell viability. However, no significant impairment of mitochondrial membrane potential (ΔΨm) was detectable. These findings indicate the potential of pathological concentrations of MMA to induce a neuronal cell CoQ10 deficiency with an associated loss of MRC complex II-III activity. However, in the absence of an impairment of ΔΨm, the contribution this potential deficit in cellular CoQ10 status makes towards the disease pathophysiology methylmalonic acidemia has yet to be fully elucidated. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/33266298/The_Effect_of_Methylmalonic_Acid_Treatment_on_Human_Neuronal_Cell_Coenzyme_Q10_Status_and_Mitochondrial_Function_ L2 - https://www.mdpi.com/resolver?pii=ijms21239137 DB - PRIME DP - Unbound Medicine ER -