Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

Abstract

Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5′-UTRs that likely improve translational efficiency, and stabilization of 3′-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD+ redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.

Leigh syndrome: One disorder, more than 75 monogenic causes

“…This is supported by transcriptomic studies of cells and tissues from mitochondrial disease patients demonstrating tissue-specific patterns of transcriptional dysregulation. 94 …”

“…Recent studies have demonstrated that PDHc and OXPHOS defects can induce transcriptional dysregulation of multiple cellular pathways including those that regulate RNA and protein metabolism. 94 These disturbances in cellular metabolism appear to be primarily mediated by effects on pathways responsible for sensing and responding to nutrient availability, including effects on the expression and activity of regulator of cellular growth mTORC1. 94 Treatment with rapamycin, an inhibitor of mTORC1, improved lifespan and attenuated neurodegeneration in the Ndufs4 knockout mouse model of LS, 97 supporting the notion that dysregulation of these pathways contributes to pathogenesis.…”

“…94 These disturbances in cellular metabolism appear to be primarily mediated by effects on pathways responsible for sensing and responding to nutrient availability, including effects on the expression and activity of regulator of cellular growth mTORC1. 94 Treatment with rapamycin, an inhibitor of mTORC1, improved lifespan and attenuated neurodegeneration in the Ndufs4 knockout mouse model of LS, 97 supporting the notion that dysregulation of these pathways contributes to pathogenesis. More recently, improvement in mitochondrial cristae morphology was observed to modestly but significantly improve motor performance, lifespan, and complex I activity in Ndufs4 knockout mice, 98 suggesting that effects on mitochondrial morphology may additionally contribute to disease pathology.…”

“…105 This redox imbalance may lead to dysregulation of the signaling pathways related to nutrient sensing referred to earlier. 94 Alleviation of oxidative stress has therefore emerged as a promising avenue of therapy for LS and other mitochondrial diseases, including the development of antioxidants EPI-743 and RP103, which are currently being examined in clinical trials. 109 Increased ROS are also implicated in the activation of inflammatory pathways that may in turn alter mitochondrial function and produce a state of chronic stress that further compromises cellular function.…”

Targeting Warburg Effect in Cancers with PEGylated Glucose

“…Various bioinformatic analyses of transcriptome data sets of the mitochondrial dysfunction indicate that the central pathway related to ATP-generating network lies with AKT/mTORC (mammalian target of rapamycin complex) pathways. [ 18,19 ] Considering the involvement of AKT in both ATP generation and the inhibition of apoptosis in cells, we investigated the mechanism of PEGylated glucose action by probing the protein/expression of AKT1 and some apoptotic markers. Our results indicated that application of PEGylated glucose led to a 50% decrease of pAKT levels at the protein level, in correlation with an increase in cell death.…”