bims-smemid 2023-08-20 papers

bioRxiv. 2023 Aug 04. pii: 2023.08.02.551712. [Epub ahead of print]

Lactate activates the mitochondrial electron transport chain independent of its metabolism.

Xin Cai, Charles C Ng, Olivia Jones, Tak Shun Fung, Keunwoo Ryu, Dayi Li, Craig B Thompson.

Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

DOI: https://doi.org/10.1101/2023.08.02.551712

Mol Cell Neurosci. 2023 Aug 15. pii: S1044-7431(23)00081-7. [Epub ahead of print]126 103887

Glutamine metabolism in diseases associated with mitochondrial dysfunction.

Rebecca Bornstein, Michael T Mulholland, Margaret Sedensky, Phil Morgan, Simon C Johnson.

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.

Keywords: Glutamine toxicity; Mitochondrial disease; Neurodegenerative disease

DOI: https://doi.org/10.1016/j.mcn.2023.103887

CNS Neurosci Ther. 2023 Aug 14.

The potential role of glucose metabolism, lipid metabolism, and amino acid metabolism in the treatment of Parkinson's disease.

Hangzhen Li, Fancai Zeng, Cancan Huang, Qiqi Pu, Elizabeth Rosalind Thomas, Yan Chen, Xiang Li.

PURPOSE OF REVIEW: Parkinson's disease (PD) is a common neurodegenerative disease, which can cause progressive deterioration of motor function causing muscle stiffness, tremor, and bradykinesia. In this review, we hope to describe approaches that can improve the life of PD patients through modifications of energy metabolism.RECENT FINDINGS: The main pathological features of PD are the progressive loss of nigrostriatal dopaminergic neurons and the production of Lewy bodies. Abnormal aggregation of α-synuclein (α-Syn) leading to the formation of Lewy bodies is closely associated with neuronal dysfunction and degeneration. The main causes of PD are said to be mitochondrial damage, oxidative stress, inflammation, and abnormal protein aggregation. Presence of abnormal energy metabolism is another cause of PD. Many studies have found significant differences between neurodegenerative diseases and metabolic decompensation, which has become a biological hallmark of neurodegenerative diseases.
SUMMARY: In this review, we highlight the relationship between abnormal energy metabolism (Glucose metabolism, lipid metabolism, and amino acid metabolism) and PD. Improvement of key molecules in glucose metabolism, fat metabolism, and amino acid metabolism (e.g., glucose-6-phosphate dehydrogenase, triglycerides, and levodopa) might be potentially beneficial in PD. Some of these metabolic indicators may serve well during the diagnosis of PD. In addition, modulation of these metabolic pathways may be a potential target for the treatment and prevention of PD.

Keywords: Parkinson's disease; amino acid metabolism; glucose metabolism; lipid metabolism

DOI: https://doi.org/10.1111/cns.14411