Complementary RNA and Protein Profiling Identifies Iron as a Key Regulator of Mitochondrial Biogenesis
ABSTRACT Mitochondria are centers of metabolism and signaling whose content and function must adapt to changing cellular environments. The biological signals that initiate mitochondrial restructuring and the cellular processes that drive this adaptive response are largely obscure. To better define these systems, we performed matched quantitative genomic and proteomic analyses of mouse muscle cells as they performed mitochondrial biogenesis. We find that proteins involved in cellular iron homeostasis are highly coordinated with this process and that depletion of cellular iron results in a rapid, dose-dependent decrease of select mitochondrial protein levels and oxidative capacity. We further show that this process is universal across a broad range of cell types and fully reversed when iron is reintroduced. Collectively, our work reveals that cellular iron is a key regulator of mitochondrial biogenesis, and provides quantitative data sets that can be leveraged to explore posttranscriptional and posttranslational processes that are essential for mitochondrial adaptation.
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ABSTRACT: Mitochondria play a central role not only in energy production but also in the integration of metabolic pathways as well as signals for apoptosis and autophagy. It is becoming increasingly apparent that mitochondria in mammalian cells play critical roles in the initiation and propagation of various signaling cascades. In particular, mitochondrial metabolic and respiratory states and status on mitochondrial genetic instability are communicated to the nucleus as an adaptive response through retrograde signaling. Each mammalian cell contains multiple copies of mitochondrial genome (mtDNA). A reduction in mtDNA copy number has been reported in various human pathological conditions such as diabetes, obesity, neurodegenerative disorders, aging and cancer. Reduction in mtDNA copy number disrupts mitochondrial membrane potential (Δψm) resulting in dysfunctional mitochondria. Dysfunctional mitochondria trigger retrograde signaling and communicate their changing metabolic and functional state to the nucleus as an adaptive response resulting in altered nuclear gene expression profile and altered cell physiology and morphology. In this review, we provide an overview of the various modes of mitochondrial retrograde signaling focusing particularly on the Ca(2+)/Calcineurin mediated retrograde signaling. We discuss the contribution of the key factors of the pathway such as Calcineurin, IGF1 receptor, Akt kinase and HnRNPA2 in the propagation of signaling and their role in modulating genetic and epigenetic changes favoring cellular reprogramming towards tumorigenesis.Mitochondrion 09/2013; 13(6). DOI:10.1016/j.mito.2013.08.007 · 3.52 Impact Factor
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ABSTRACT: Severe copper deficiency leads to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated in humans. We tested whether copper deficit leads to alterations in fundamental copper dependent proteins and in iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy, and if these metabolic abnormalities are associated with compensatory mechanisms for copper maintenance. We evaluated the expression of critical copper-enzymes, of iron-related proteins, and copper chaperones and transporters in blood and muscles from five copper deficient patients presenting with subacute sensory ataxia, muscle paralysis, steatosis, and variable anaemia. Severe copper deficiency was caused by chronic zinc intoxication in all of the patients, with an additional history of gastrectomy in two cases. The antioxidant enzyme SOD1 and subunit 2 of cytochrome c oxidase were significantly decreased in blood cells and in muscles of copper-deficient patients compared to controls. In muscle, the iron storage protein ferritin was dramatically reduced despite normal serum ferritin, and the expression of the heme-proteins cytochrome c and myoglobin was impaired. Muscle expression of the copper transporter CTR1 and of the copper chaperone CCS, were strikingly increased, while antioxidant protein 1 was diminished. Critical copper-dependent enzymes involved in antioxidant defenses, in mitochondrial energy production, and in iron metabolism are affected in blood cells and muscles of patients with profound copper deficiency leading to myeloneuropathy. Homeostatic mechanisms are strongly activated to increase intracellular copper retention.Neuropathology and Applied Neurobiology 12/2013; 40(7). DOI:10.1111/nan.12111 · 4.97 Impact Factor
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ABSTRACT: Altered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions in order to examine their effects on cellular ATP levels. We identified a mechanism by which electron transport chain (ETC) perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux, thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels and AMPK signaling and whose expression significantly correlates with glioma patient survival. This study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.03.065 · 8.36 Impact Factor