Scholarlink

<p>Type 2 diabetes (T2D) is driven by pancreatic β-cell failure, often in the metabolic context of overweight, obesity, and systemic insulin resistance. Importantly, the accumulation of excess lipids in the pancreas accelerates mitochondrial dysfunction and imbalanced dynamics, both of which are considered early indicators of T2D. The availability of the fatty acid pool determines the composition of cardiolipins (CLs), signature mitochondrial phospholipids. Stearoyl-coenzyme A desaturase 1 (SCD1) remains the lynchpin metabolic enzyme that is responsible for the equipoise biosynthesis of monounsaturated fatty acyl moieties, thereby affecting the overall rate of β-cell survival. The present study investigated the molecular effect of SCD1 depletion on the regulation of mitochondrial energetic status and architecture in pancreatic β-cells that underwent lipotoxic insult. The ablation of SCD1 activity led to severe impairments in mitochondrial bioenergetics, indicated by compromised mitochondrial membrane potential and lower adenosine triphosphate production in opposition to INS-1E cells that were independently subjected to palmitotoxicity. This effect occurred alongside higher amounts of compromised mitochondria and alterations of CL-linked oxidative phosphorylation complexes. The β-cell and pancreatic islet fraction of CL was enriched in 16:1, 18:1, 18:2, 20:4, and 20:3n-6 fatty acids. Such lipid rearrangements coincided with abnormal CL concentrations, alterations of the abundance of CL remodeling or fatty acyl moiety distribution, and cristae shaping effectors. Increases in hallmarks of lipid peroxidation and accelerated susceptibility to ferroptosis complemented observations of the palmitate-mediated collapse of cristae microarchitecture upon SCD1 deficiency. These findings disentangle the yet uncharacterized role of Δ⁹-desaturation in counteracting lipotoxicity-derived mitochondrial decay that occurs during the gradual failure of pancreatic β-cells in T2D by integrating CL acyl-side chain composition and mitochondrial homeostasis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Compositional recalibrations of cardiolipin integrate loss of stearoyl-CoA desaturase 1 activity with mitochondrial decay in lipid-laden pancreatic β-cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月27日

查看全文
  • Justyna Janikiewicz,
  • Magdalena Lebiedzinska-Arciszewska,
  • Maria E. Kendziorek,
  • Ewelina Krogulec,
  • Katarzyna Majzner,
  • Katarzyna Kolczynska-Matysiak,
  • Mariusz R. Wieckowski,
  • Aneta M. Dobosz,
  • Agnieszka Dobrzyn

摘要

Type 2 diabetes (T2D) is driven by pancreatic β-cell failure, often in the metabolic context of overweight, obesity, and systemic insulin resistance. Importantly, the accumulation of excess lipids in the pancreas accelerates mitochondrial dysfunction and imbalanced dynamics, both of which are considered early indicators of T2D. The availability of the fatty acid pool determines the composition of cardiolipins (CLs), signature mitochondrial phospholipids. Stearoyl-coenzyme A desaturase 1 (SCD1) remains the lynchpin metabolic enzyme that is responsible for the equipoise biosynthesis of monounsaturated fatty acyl moieties, thereby affecting the overall rate of β-cell survival. The present study investigated the molecular effect of SCD1 depletion on the regulation of mitochondrial energetic status and architecture in pancreatic β-cells that underwent lipotoxic insult. The ablation of SCD1 activity led to severe impairments in mitochondrial bioenergetics, indicated by compromised mitochondrial membrane potential and lower adenosine triphosphate production in opposition to INS-1E cells that were independently subjected to palmitotoxicity. This effect occurred alongside higher amounts of compromised mitochondria and alterations of CL-linked oxidative phosphorylation complexes. The β-cell and pancreatic islet fraction of CL was enriched in 16:1, 18:1, 18:2, 20:4, and 20:3n-6 fatty acids. Such lipid rearrangements coincided with abnormal CL concentrations, alterations of the abundance of CL remodeling or fatty acyl moiety distribution, and cristae shaping effectors. Increases in hallmarks of lipid peroxidation and accelerated susceptibility to ferroptosis complemented observations of the palmitate-mediated collapse of cristae microarchitecture upon SCD1 deficiency. These findings disentangle the yet uncharacterized role of Δ⁹-desaturation in counteracting lipotoxicity-derived mitochondrial decay that occurs during the gradual failure of pancreatic β-cells in T2D by integrating CL acyl-side chain composition and mitochondrial homeostasis.