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Metabolomics in the Study of Human Mitochondrial Diseases

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Clinical Metabolomics Applications in Genetic Diseases

Abstract

Mitochondria are dynamic cellular organelles playing many biological roles that are fundamentally required for cellular functions. The primary role of mitochondria is ATP production through oxidative phosphorylation (OXPHOS). Mitochondria are found in nearly all cell types, and their number within cells varies in a tissue−/organ-dependent manner. Tissues/organs characterized by high-energy demands contain abundant mitochondria, and these tissues/organs are most frequently affected when their mitochondria are dysfunctional. The resulting pathologies can be generally referred to as mitochondrial diseases (MDs). MDs can be caused by nuclear or mitochondrial DNA mutations in genes encoding mitochondrial proteins, including OXPHOS proteins. Also, MDs can be developed through nongenetic mechanisms such as those involving environmental factors, mitotoxicity drugs, oxidative stress, and aging. MDs can appear over the entire life span. Patients with particular MDs present a wide range of heterogeneous phenotypes with different levels of disease severity. The wide variety of leading causes and heterogenous phenotypes of MDs make diagnosing MDs notoriously challenging. Despite these challenges, multiple diagnostic examinations and tools, including family history, phenotypic examinations, neurological imaging, biochemical tests, and genetic analyses, have collectively enhanced the diagnosis of MDs. As a result of the diagnostic limitations and drawbacks, there have been demands for developing new diagnostic approaches capable of detecting metabolic perturbations of MDs used as metabolic biosignatures. For that reason, the metabolomic approach, the study of small metabolites ≤1500 daltons, has recently garnered attention. While metabolomics offers significant advances, it is recommended that data sets be integrated with other diagnostic approaches. This chapter reviews the application of metabolomic analyses in studying human MDs.

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Abbreviations

ANT:

Adenine nucleotide translocase

ATP:

Adenosine triphosphate

BAT:

Brown adipose tissue

CAT:

Catalase

CE-MS:

Capillary electrophoresis-coupled mass spectrometry

CIL:

Chemical isotope labeling

CPEO:

Chronic progressive external ophthalmoplegia

DRP1:

Dynamin-related protein-1

ETF:

Electron transfer flavoprotein

FIS1:

Fission protein-1

GC-MS:

Gas chromatography-coupled mass spectrometry

GPxs:

Glutathione peroxidases

GSH:

Glutathione

IMM:

Inner mitochondrial membrane

IMS:

Intermembrane space

KSS:

Kearns-Sayre syndrome

LC-MS:

Liquid chromatography-coupled mass spectrometry

LHON:

Leber hereditary optic neuropathy

MDs:

Mitochondrial diseases

MELAS:

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MERRF:

Myoclonic epilepsy with ragged-red fibers

MFF:

Mitochondrial fission factor

MFN1:

Mitofusins-1

MFN2:

Mitofusins-2

MiD49:

Mitochondrial dynamic proteins of 49 kDa

MiD51:

Mitochondrial dynamic proteins of 51 kDa

MNGIE:

Mitochondrial neurogastrointestinal encephalopathy

MS:

Mass spectrometry

mtDNA:

Mitochondrial DNA

NAC:

N-acetylcysteine

NARP:

Neuropathy, ataxia, and retinitis pigmentosa

nDNA:

Nuclear DNA

NMR:

Nuclear magnetic resonance

OMM:

Outer mitochondrial membrane

OPA1:

Optic atrophy-1

OXPHOS:

Oxidative phosphorylation

PMF:

Proton motive force

PMS:

Pearson marrow pancreas syndrome

ROS:

Reactive oxygen species

rRNA:

Ribosomal RNA

SOD:

Superoxide dismutase

SPG7:

Hereditary spastic paraplegia 7

TCA:

Tricarboxylic acid cycle

TFAM:

Transcription factor A of mitochondria

TFB2M:

Mitochondrial transcription factor B2

tRNA:

Transfer RNA

Trx:

Thioredoxin

UCP1:

Uncoupling protein-1

VUS:

Variants of uncertain significance

WES:

Whole exome sequencing

WGS:

Whole genome sequencing

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Authors and Affiliations

  1. Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Al-Dawadmi, Saudi Arabia

    Rajaa Sebaa

  2. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Mary-Ellen Harper

  3. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada

    Mary-Ellen Harper

  4. Department of Internal Medicine, King Abdullah Hospital, Bisha, Saudi Arabia

    Ruqaiah Al-Tassan

  5. Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

    Ruqaiah Al-Tassan & Mohammed Al-Owain

  6. Metabolomics Section, Department of Clinical Genomics, Center for Genome Medicine, King Faisal Specialist Hospital & Research Center (KFSHRC), Riyadh, Saudi Arabia

    Anas M. Abdel Rahman

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  1. Rajaa Sebaa
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  1. Metabolomics Section, Department of Clinical Genomics, Center for Genome Medicine, King Faisal Specialist Hospital & Research Center (KFSHRC), Riyadh, Saudi Arabia

    Anas M. Abdel Rahman

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Sebaa, R., Harper, ME., Al-Tassan, R., Al-Owain, M., Abdel Rahman, A.M. (2023). Metabolomics in the Study of Human Mitochondrial Diseases. In: Abdel Rahman, A.M. (eds) Clinical Metabolomics Applications in Genetic Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-99-5162-8_7

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