Abstract
Disorders of mitochondrial fat metabolism lead to sudden death in infants and children. Although survival is possible, the underlying molecular mechanisms which enable this outcome have not yet been clearly identified. Here we describe a conserved genetic network linking disorders of mitochondrial fat metabolism in mice to mechanisms of fat storage and survival in Caenorhabditis elegans (C. elegans). We have previously documented a mouse model of mitochondrial very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency.[1] We originally reported that the mice survived birth, but, upon exposure to cold and fasting stresses, these mice developed cardiac dysfunction, which greatly reduced survival. We used cDNA microarrays[2], [3], [4] to outline the induction of several markers of lipid metabolism in the heart at birth in surviving mice. We hypothesized that the induction of fat metabolism genes in the heart at birth is part of a regulatory feedback circuit that plays a critical role in survival.[1] The present study uses a dual approach employing both C57BL/6 mice and the nematode, C. elegans, to focus on TMEM135, a conserved protein which we have found to be upregulated 4.3 (±0.14)-fold in VLCAD-deficient mice at birth. Our studies have demonstrated that TMEM135 is highly expressed in mitochondria and in fat-loaded tissues in the mouse. Further, when fasting and cold stresses were introduced to mice, we observed 3.25 (±0.03)- and 8.2 (±0.31)- fold increases in TMEM135 expression in the heart, respectively. Additionally, we found that deletion of the tmem135 orthologue in C. elegans caused a 41.8% (±2.8%) reduction in fat stores, a reduction in mitochondrial action potential and decreased longevity of the worm. In stark contrast, C. elegans transgenic animals overexpressing TMEM-135 exhibited increased longevity upon exposure to cold stress. Based on these results, we propose that TMEM135 integrates biological processes involving fat metabolism and energy expenditure in both the worm (invertebrates) and in mammalian organisms. The data obtained from our experiments suggest that TMEM135 is part of a regulatory circuit that plays a critical role in the survival of VLCAD-deficient mice and perhaps in other mitochondrial genetic defects of fat metabolism as well.
Highlights
The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step in the mitochondrial fatty acid b-oxidation spiral
The induction of these genes at birth further supported our hypothesis that the induction of these fat metabolism genes in the heart at birth is part of a feedback-regulated circuit that plays a critical role in survival in VLCAD deficiency
We previously reported on a mouse model of VLCAD deficiency[1,10,23] that exhibited lipid accumulation in the heart as well as the marked induction of several indictors of lipid metabolism at birth, including PPARa, adipophilin and acyl-CoA synthase prior to any microscopic evidence of lipid droplets in the heart.[1]
Summary
The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step in the mitochondrial fatty acid b-oxidation spiral. It is well documented that mutation in the VLCAD gene leads to cardiomyopathy, skeletal myopathy, encephalopathy and sudden death in children and young adults.[5,6,7,8,9] Our previously published data on VLCAD-deficient mice showed that when the fasting and cold stresses were introduced, these animals exhibited decreased survival, recapitulating the clinical phenotypes of children with VLCAD deficiency.[10] In a previous study[1], we documented that, at birth, the surviving mice showed marked upregulation of both the peroxisome proliferator-activated receptorc (PPARc) coactivator-1 alpha (PGC-1a), which is a critical regulator of mitochondrial biogenesis, as well as acyl-CoA synthase, which is a facilitator of sarcolemmal fatty acid uptake.[1] The induction of these genes at birth further supported our hypothesis that the induction of these fat metabolism genes in the heart at birth is part of a feedback-regulated circuit that plays a critical role in survival in VLCAD deficiency Another protein, TMEM135, which had not been previously characterized, was found to be elevated in VLCAD-deficient mice on the first day of life. Due to the fact that TMEM135 was found to be phylogenetically highly conserved, we hypothesized that the regulatory feedback circuit to which it belongs, as well as its function, might be conserved
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