Cover Story Current Issue
Excessive lipid accumulation in adipose tissue triggers hypertrophy and stress of adipocytes, leading to infiltration of proinflammatory immune cells, fibrosis and adipocyte cell death, collectively referred to as adipose tissue dysfunction. As consequence, adipocytes capacity to store lipids is impaired and fat is ectopically accumulated in organs such as muscle, liver and pancreas, a condition that promotes organ dysfunction and insulin resistance, contributing to the pathogenesis of type 2 diabetes (T2D).
Although fat accumulation in human pancreas was described decades ago, it has for long remained an underexplored facet of ectopic fat distribution. Pancreatic fat has been associated with improved insulin secretion in normoglycaemic subjects, but with impaired insulin secretion in patients at increased risk of T2D. Furthermore, T2D diabetes remission, i.e. recovery of beta cell function was accompanied by reduction of pancreatic fat. These clinical observations point to the controversial role of pancreatic fat in insulin secretion, and emphasize the need for experimental evidence demonstrating plausible lipolysis derived fatty acids-/secretome-mediated effects of pancreatic adipocytes in islets. To date, detailed studies on the mechanistic interactions between pancreatic adipocytes and insulin secretion remain sparse, as reliable in vitro models replicating the unique properties of these cells have been lacking.
Current Issue
Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport
Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport
Objective
Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency.
Methods
We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport activity and calcium regulation of wild-type citrin and pathogenic variants associated with citrin deficiency. We have also developed a double knockout of citrin and aralar (AGC1), the two paralogs of the mitochondrial aspartate/glutamate carrier, in HAP1 cells to perform mitochondrial imaging and to investigate mitochondrial localisation.
Results
Using 33 pathogenic variants of citrin we clarify determinants of subcellular localization and transport mechanism. We identify crucial elements of the carrier domain that are required for transport, including those involved in substrate binding, network formation and dynamics. We show that the N-terminal domain is not involved in calcium regulation of transport, as previously thought, but when mutated causes a mitochondrial import defect.
Conclusions
Our work introduces a new role for the N-terminal domain of citrin and demonstrates that dysfunction of the different domains contributes to distinct pathogenic mechanisms in citrin deficiency.
Articles in Press
Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport
Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport
Objective
Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency.
Methods
We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport activity and calcium regulation of wild-type citrin and pathogenic variants associated with citrin deficiency. We have also developed a double knockout of citrin and aralar (AGC1), the two paralogs of the mitochondrial aspartate/glutamate carrier, in HAP1 cells to perform mitochondrial imaging and to investigate mitochondrial localisation.
Results
Using 33 pathogenic variants of citrin we clarify determinants of subcellular localization and transport mechanism. We identify crucial elements of the carrier domain that are required for transport, including those involved in substrate binding, network formation and dynamics. We show that the N-terminal domain is not involved in calcium regulation of transport, as previously thought, but when mutated causes a mitochondrial import defect.
Conclusions
Our work introduces a new role for the N-terminal domain of citrin and demonstrates that dysfunction of the different domains contributes to distinct pathogenic mechanisms in citrin deficiency.
You are what you eat
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