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Evolutionary forces have wired our brains to prefer and consume energy-dense foods to aid in our survival. While effective during periods of limited access, the ubiquitous nature of high-fat food sources in society leads to obesity and numerous related health complications. Exacerbating this drive to consume more energy-dense, palatable foods is a devaluation of less appetitive, nutritionally-balanced foods. While this preference for calorically-rich foods is well known, significant gaps exist in our understanding of how this develops and leads to devaluation.

Laboratory mice are typically provided with ad libitum access to a well-balanced standard chow diet (SD) in which the macronutrient composition has been formulated for optimal growth. Introduction to ad libitum high fat diet (HFD), but not a high-sucrose diet, leads to rapid weight gain, at least in part due to excessive caloric intake. Interestingly, when mice are given a choice between ad libitum access to both SD and HFD, they strongly prefer consumption of the latter at the expense of the former. While this predilection for HFD over SD during prolonged exposure is well described, how rapidly this transition occurs under physiological or artificial hunger is less known. Removal of HFD from mice given the choice between HFD and SD, akin to a strict human diet, results in rapid weight loss due to the self-restricted consumption of SD. Additionally, mice fed a HFD will forgo SD consumption even in states of physiological or artificially-induced caloric deprivation. While this SD devaluation is robustly conserved between sex and subject and independent of fat mass accrual, the causative nature of this phenomenon is not well understood.

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HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

Cagla Cömert, Kasper Kjær-Sørensen, Jakob Hansen, Jasper Carlsen, ... Peter Bross

HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

 

Objective

Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 is essential for cell function and dysregulation of HSP60 expression has been implicated in cancer and diabetes. The few reported patients carrying HSP60 gene variants show neurodevelopmental delay and brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the mitochondrial proteins and functions affected by HSP60 deficiency are poorly characterized.

Methods

We studied two model systems for HSP60 deficiency: (1) engineered HEK cells carrying an inducible dominant negative HSP60 mutant protein, (2) zebrafish HSP60 knockout larvae. Both systems were analyzed by RNASeq, proteomics, and targeted metabolomics, and several functional assays relevant for the respective model. In addition, skin fibroblasts from patients with disease-associated HSP60 variants were analyzed by proteomics.

Results

We show that HSP60 deficiency leads to a differentially downregulated mitochondrial matrix proteome, transcriptional activation of stress responses, and dysregulated cholesterol biosynthesis. This leads to lipid accumulation in zebrafish knockout larvae.

Conclusions

Our data provide a compendium of the effects of HSP60 deficiency on the mitochondrial matrix proteome. We show that HSP60 is a master regulator and modulator of mitochondrial functions and metabolic pathways. HSP60 dysfunction also affects cellular metabolism and disrupts the integrated stress response. The effect on cholesterol synthesis explains the effect of HSP60 dysfunction on myelination observed in patients carrying genetic variants of HSP60.

 

 

Articles in Press

HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

Cagla Cömert, Kasper Kjær-Sørensen, Jakob Hansen, Jasper Carlsen, ... Peter Bross

HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

 

Objective

Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 is essential for cell function and dysregulation of HSP60 expression has been implicated in cancer and diabetes. The few reported patients carrying HSP60 gene variants show neurodevelopmental delay and brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the mitochondrial proteins and functions affected by HSP60 deficiency are poorly characterized.

Methods

We studied two model systems for HSP60 deficiency: (1) engineered HEK cells carrying an inducible dominant negative HSP60 mutant protein, (2) zebrafish HSP60 knockout larvae. Both systems were analyzed by RNASeq, proteomics, and targeted metabolomics, and several functional assays relevant for the respective model. In addition, skin fibroblasts from patients with disease-associated HSP60 variants were analyzed by proteomics.

Results

We show that HSP60 deficiency leads to a differentially downregulated mitochondrial matrix proteome, transcriptional activation of stress responses, and dysregulated cholesterol biosynthesis. This leads to lipid accumulation in zebrafish knockout larvae.

Conclusions

Our data provide a compendium of the effects of HSP60 deficiency on the mitochondrial matrix proteome. We show that HSP60 is a master regulator and modulator of mitochondrial functions and metabolic pathways. HSP60 dysfunction also affects cellular metabolism and disrupts the integrated stress response. The effect on cholesterol synthesis explains the effect of HSP60 dysfunction on myelination observed in patients carrying genetic variants of HSP60.

 

 

You are what you eat

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