TY - JOUR
T1 - Glutamine metabolism in diseases associated with mitochondrial dysfunction
AU - Bornstein, Rebecca L.
AU - Mulholland, Michael T.
AU - Sedensky, Margaret M.
AU - Morgan, Phil G.
AU - Johnson, Simon C.
N1 - Funding information: SCJ was funded by R01GM133865, R01NS119426, and R01GM144368. MS was funded by R01GM133865. RB was funded by NIH T32GM095421 and 1F31NS120442.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.
AB - Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.
KW - Mitochondrial disease
KW - Glutamine toxicity
KW - Neurodegenerative disease
UR - http://www.scopus.com/inward/record.url?scp=85168000236&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2023.103887
DO - 10.1016/j.mcn.2023.103887
M3 - Review article
SN - 1044-7431
VL - 126
JO - Molecular and Cellular Neurosciences
JF - Molecular and Cellular Neurosciences
M1 - 103887
ER -