Biomarkers of Mitochondrial Disorders

Overview

Journal Neurotherapeutics

Specialty Neurology

Date 2024 Jan 31

PMID 38295557

Authors

Brian J Shayota

Affiliations

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Abstract

Mitochondrial diseases encompass a heterogeneous group of disorders with a wide range of clinical manifestations, most classically resulting in neurological, muscular, and metabolic abnormalities, but having the potential to affect any organ system. Over the years, substantial progress has been made in identifying and characterizing various biomarkers associated with mitochondrial diseases. This review summarizes the current knowledge of mitochondrial biomarkers based on a literature review and discusses the evidence behind their use in clinical practice. A total of 13 biomarkers were thoroughly reviewed including lactate, pyruvate, lactate:pyruvate ratio, creatine kinase, creatine, amino acid profiles, glutathione, malondialdehyde, GDF-15, FGF-21, gelsolin, neurofilament light-chain, and circulating cell-free mtDNA. Most biomarkers had mixed findings depending on the study, especially when considering their utility for specific mitochondrial diseases versus mitochondrial conditions in general. However, in large biomarker comparison studies, GDF-15 followed by FGF-21, seem to have the greatest value though they are still not perfect. As such, additional studies are needed, especially in light of newer biomarkers that have not yet been thoroughly investigated. Understanding the landscape of biomarkers in mitochondrial diseases is crucial for advancing early detection, improving patient management, and developing targeted therapies.

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References

El-Hattab A, Hsu J, Emrick L, Wong L, Craigen W, Jahoor F . Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol Genet Metab. 2012; 105(4):607-14. PMC: 4093801. DOI: 10.1016/j.ymgme.2012.01.016. View

Heinicke K, Taivassalo T, Wyrick P, Wood H, Babb T, Haller R . Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms. Am J Physiol Regul Integr Comp Physiol. 2011; 301(4):R873-84. PMC: 3197343. DOI: 10.1152/ajpregu.00001.2011. View

Koene S, de Laat P, van Tienoven D, Weijers G, Vriens D, Sweep F . Serum GDF15 Levels Correlate to Mitochondrial Disease Severity and Myocardial Strain, but Not to Disease Progression in Adult m.3243A>G Carriers. JIMD Rep. 2015; 24:69-81. PMC: 4582022. DOI: 10.1007/8904_2015_436. View

Coskun T, Bina H, Schneider M, Dunbar J, Hu C, Chen Y . Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008; 149(12):6018-27. DOI: 10.1210/en.2008-0816. View

Salehi M, Kamalidehghan B, Houshmand M, Aryani O, Sadeghizadeh M, Mossalaeie M . Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich Ataxia). Mol Biol Rep. 2013; 40(11):6495-9. PMC: 3824290. DOI: 10.1007/s11033-013-2767-0. View

Zhang J, Guo J, Fang W, Jun Q, Shi K . Clinical features of MELAS and its relation with A3243G gene point mutation. Int J Clin Exp Pathol. 2016; 8(10):13411-5. PMC: 4680494. View

Evangelisti S, Gramegna L, La Morgia C, Di Vito L, Maresca A, Talozzi L . Molecular biomarkers correlate with brain grey and white matter changes in patients with mitochondrial m.3243A > G mutation. Mol Genet Metab. 2021; 135(1):72-81. DOI: 10.1016/j.ymgme.2021.11.012. View

Ito F, Sono Y, Ito T . Measurement and Clinical Significance of Lipid Peroxidation as a Biomarker of Oxidative Stress: Oxidative Stress in Diabetes, Atherosclerosis, and Chronic Inflammation. Antioxidants (Basel). 2019; 8(3). PMC: 6466575. DOI: 10.3390/antiox8030072. View

Piccolo G, Banfi P, Azan G, Rizzuto R, Bisson R, Sandona D . Biological markers of oxidative stress in mitochondrial myopathies with progressive external ophthalmoplegia. J Neurol Sci. 1991; 105(1):57-60. DOI: 10.1016/0022-510x(91)90118-q. View

10.

Karppa M, Mahjneh I, Karttunen A, Tolonen U, Majamaa K . Muscle computed tomography patterns in patients with the mitochondrial DNA mutation 3243A>G. J Neurol. 2004; 251(5):556-63. DOI: 10.1007/s00415-004-0363-x. View

11.

Kharitonenkov A, Wroblewski V, Koester A, Chen Y, Clutinger C, Tigno X . The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology. 2006; 148(2):774-81. DOI: 10.1210/en.2006-1168. View

12.

Yu X, Yan C, Ji K, Lin P, Xu X, Dai T . Clinical, Neuroimaging, and Pathological Analyses of 13 Chinese Leigh Syndrome Patients with Mitochondrial DNA Mutations. Chin Med J (Engl). 2018; 131(22):2705-2712. PMC: 6247594. DOI: 10.4103/0366-6999.245265. View

13.

Glancy B, Kane D, Kavazis A, Goodwin M, Willis W, Gladden L . Mitochondrial lactate metabolism: history and implications for exercise and disease. J Physiol. 2020; 599(3):863-888. PMC: 8439166. DOI: 10.1113/JP278930. View

14.

Garcia-Bartolome A, Penas A, Illescas M, Bermejo V, Lopez-Calcerrada S, Perez-Perez R . Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction. Cells. 2020; 9(9). PMC: 7563380. DOI: 10.3390/cells9091922. View

15.

Shatla H, Tomoum H, Elsayed S, Elagouza I, Shatla R, Mohsen M . Role of plasma amino acids and urinary organic acids in diagnosis of mitochondrial diseases in children. Pediatr Neurol. 2014; 51(6):820-5. DOI: 10.1016/j.pediatrneurol.2014.08.009. View

16.

Clarke C, Xiao R, Place E, Zhang Z, Sondheimer N, Bennett M . Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites. Mol Genet Metab. 2013; 110(1-2):145-52. PMC: 3812452. DOI: 10.1016/j.ymgme.2013.07.011. View

17.

Koene S, de Laat P, van Tienoven D, Vriens D, Brandt A, Sweep F . Serum FGF21 levels in adult m.3243A>G carriers: clinical implications. Neurology. 2014; 83(2):125-33. DOI: 10.1212/WNL.0000000000000578. View

18.

McClintock C, Mulholland N, Krasnodembskaya A . Biomarkers of mitochondrial dysfunction in acute respiratory distress syndrome: A systematic review and meta-analysis. Front Med (Lausanne). 2023; 9:1011819. PMC: 9795057. DOI: 10.3389/fmed.2022.1011819. View

19.

Fon Tacer K, L Bookout A, Ding X, Kurosu H, John G, Wang L . Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol. 2010; 24(10):2050-64. PMC: 2954642. DOI: 10.1210/me.2010-0142. View

20.

Feldman A, Sokol R, Hardison R, Alonso E, Squires R, Narkewicz M . Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure. J Pediatr. 2017; 182:217-222.e3. PMC: 5328928. DOI: 10.1016/j.jpeds.2016.12.031. View