RESUMEN
Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.
Asunto(s)
Proteasas ATP-Dependientes , ATPasas Asociadas con Actividades Celulares Diversas , Glutatión , Mitocondrias , Proteínas Mitocondriales , Proteínas de Transporte de Fosfato , Glutatión/metabolismo , Homeostasis , Hierro/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteómica , Retroalimentación Fisiológica , Proteínas Mitocondriales/metabolismo , Proteínas de Transporte de Fosfato/metabolismo , Humanos , Proteínas Hierro-Azufre/metabolismo , Proteolisis , Células HEK293 , Proteasas ATP-Dependientes/genética , Proteasas ATP-Dependientes/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismoRESUMEN
In the version of this Letter originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Letter.
RESUMEN
As oxygen is essential for many metabolic pathways, tumour hypoxia may impair cancer cell proliferation1-4. However, the limiting metabolites for proliferation under hypoxia and in tumours are unknown. Here, we assessed proliferation of a collection of cancer cells following inhibition of the mitochondrial electron transport chain (ETC), a major metabolic pathway requiring molecular oxygen5. Sensitivity to ETC inhibition varied across cell lines, and subsequent metabolomic analysis uncovered aspartate availability as a major determinant of sensitivity. Cell lines least sensitive to ETC inhibition maintain aspartate levels by importing it through an aspartate/glutamate transporter, SLC1A3. Genetic or pharmacologic modulation of SLC1A3 activity markedly altered cancer cell sensitivity to ETC inhibitors. Interestingly, aspartate levels also decrease under low oxygen, and increasing aspartate import by SLC1A3 provides a competitive advantage to cancer cells at low oxygen levels and in tumour xenografts. Finally, aspartate levels in primary human tumours negatively correlate with the expression of hypoxia markers, suggesting that tumour hypoxia is sufficient to inhibit ETC and, consequently, aspartate synthesis in vivo. Therefore, aspartate may be a limiting metabolite for tumour growth, and aspartate availability could be targeted for cancer therapy.
Asunto(s)
Ácido Aspártico/metabolismo , Proliferación Celular , Metabolismo Energético , Neoplasias/metabolismo , Hipoxia Tumoral , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/farmacología , Transporte Biológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Metabolismo Energético/efectos de los fármacos , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 1 de Aminoácidos Excitadores/metabolismo , Humanos , Metabolómica/métodos , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Transducción de Señal , Factores de Tiempo , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.