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Glycyrrhetinic acid restricts mitochondrial energy metabolism through targeting SHMT2

ABSTRACT: Mitochondria are cell’s powerhouses to provide energy and essential metabolic intermediates to ensure cellular functions, and its dysregulation plays an important role during tumorigenesis. Targeting mitochondria is a promising approach for cancer therapy. Glycyrrhetinic acid (GA) is a natural product with mitochondria-targeting property and shows broad anti-cancer activities, but its targets and underlying mechanisms remain elusive. Here we identify the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) as a target of GA by using chemical proteomics. Binding to and inhibiting the catalytic activity of SHMT2 by GA are systematically validated in vitro and in vivo. Knockout of SHMT2 or inhibiting SHMT2 with GA restricts mitochondrial energy supplies through down-regulating mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation, and consequently suppresses cancer cell proliferation and tumor growth in xenograft mice. Crystal structures of GA derivatives indicate that GA can sit into folate-binding pocket of SHMT2 and regulate SHMT2 activity. Besides, chemical modifications at the carboxylic group of GA with diamines allows to significantly improve its anti-cancer potency, demonstrating GA as a decent structural template for SHMT2 inhibitor development. Collectively, these findings reveal the precise mechanism of action of GA that could be a promising drug lead for targeted therapies of certain cancers.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lunzhi Dai

PROVIDER: PXD031021 | iProX | Sun Jan 16 00:00:00 GMT 2022

REPOSITORIES: iProX

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Project description:Mitochondrial diseases are caused by dysfunction of the mitochondria, which are specialized compartments that are present in every cell of the body except red blood cells. Mitochondria generate more than 90% of the energy that the body needs to sustain life and support growth. When they fail, less and less energy is generated within the cell. This injures the cell and can cause its death. If this process is repeated throughout the body, whole organ systems begin to fail, and the life of the person in whom this is happening is severely compromised. Mitochondrial diseases primarily affect children, but adult onset is becoming more and more common. Mitochondrial diseases are probably the most diverse human disorders at every level: clinical, biochemical, and genetic. Some affect only the nervous system but most affect many body systems, including the brain, heart, liver, skeletal muscles, kidney, and the endocrine and respiratory systems. Although mitochondrial disorders vary in severity, they are usually progressive, and often crippling. They can cause paralysis, seizures, mental retardation, dementia, hearing loss, blindness, weakness and premature death. Because of the range of symptoms and the frequent involvement of multiple body systems, mitochondrial diseases can be a great challenge to diagnose. Even when accurately diagnosed, they pose an even more formidable challenge to treat, as there are very few therapies and most are only partially effective. About this Study The first objective of this study is to establish a clinical registry of patients with suspected or confirmed mitochondrial diseases. We are collecting medical and family history, diagnostic test results, and prospective medical information for these patients and, using agreed procedures developed by the leading research clinicians in the field, providing, for the first time, standardized diagnoses of these complex disorders for the patients. The clinical information we collect from the participants will be used to learn about the spectrum of mitochondrial disorders and their prevalence. We will also develop studies which allow us to better understand how these diseases progress, which we do not understand well enough. When we begin clinical trials for mitochondrial diseases, patients enrolled in the registry who are identified as potentially eligible will be offered enrollment. Patients will only be included in studies if they give their consent in advance. The second objective of this study is to establish a biorepository for specimens and DNA from patients with mitochondrial diseases, in order to make materials easily available to consortium researchers.

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Glycyrrhetinic acid restricts mitochondrial energy metabolism through targeting SHMT2

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