The potential causes of cystic fibrosis-related diabetes

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD

Humoral responses to the measles, mumps and rubella vaccine are impaired in Leigh Syndrome French Canadian patients

Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry mutations in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell types including the differentiation and function of immune cells. Hence, we postulated that, in addition to neurological and metabolic disorders, LSFC patients may show impaired immune activity. To gain insight into the quality of the immune response in LSFC patients, we examined the response to the measles, mumps and rubella (MMR) vaccine by measuring antibody titers to MMR in the plasma. In a cohort of eight LSFC patients, the response to the MMR vaccine was variable, with some individuals showing antibodies to all three viruses, while others had antibodies to two or fewer viruses. These results suggest that the mutations in the LRPPRC gene present in LSFC patients may affect the immune response to vaccines. Monitoring vaccine response in this fragile population should be considered to ensure full protection against pathogens

Mitochondrial Vulnerability and Increased Susceptibility to Nutrient-Induced Cytotoxicity in Fibroblasts from Leigh Syndrome French Canadian Patients

<div><p>Mutations in LRPPRC are responsible for the French Canadian variant of Leigh Syndrome (LSFC), a severe disorder characterized biochemically by a tissue-specific deficiency of cytochrome c oxidase (COX) and clinically by the occurrence of severe and deadly acidotic crises. Factors that precipitate these crises remain unclear. To better understand the physiopathology and identify potential treatments, we performed a comprehensive analysis of mitochondrial function in LSFC and control fibroblasts. Furthermore, we have used this cell-based model to screen for conditions that promote premature cell death in LSFC cells and test the protective effect of ten interventions targeting well-defined aspects of mitochondrial function. We show that, despite maintaining normal ATP levels, LSFC fibroblasts present several mitochondrial functional abnormalities under normal baseline conditions, which likely impair their capacity to respond to stress. This includes mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, lower membrane potential, increased sensitivity to Ca²⁺-induced permeability transition, but no changes in reactive oxygen species production. We also show that LSFC fibroblasts display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral. Furthermore, we demonstrate that compounds that are known to promote flux through the electron transport chain independent of phosphorylation (methylene blue, dinitrophenol), or modulate fatty acid (L-carnitine) or Krebs cycle metabolism (propionate) are protective, while antioxidants (idebenone, N-acetyl cysteine, resveratrol) exacerbate palmitate plus lactate-induced cell death. Collectively, beyond highlighting multiple alterations in mitochondrial function and increased susceptibility to nutrient-induced cytotoxicity in LSFC fibroblasts, these results raise questions about the nature of the diets, particularly excess fat intake, as well as on the use of antioxidants in patients with LSFC and, possibly, other COX defects.</p></div

Humoral responses to the measles, mumps and rubella vaccine are impaired in Leigh Syndrome French Canadian patients.

Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry mutations in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell types including the differentiation and function of immune cells. Hence, we postulated that, in addition to neurological and metabolic disorders, LSFC patients may show impaired immune activity. To gain insight into the quality of the immune response in LSFC patients, we examined the response to the measles, mumps and rubella (MMR) vaccine by measuring antibody titers to MMR in the plasma. In a cohort of eight LSFC patients, the response to the MMR vaccine was variable, with some individuals showing antibodies to all three viruses, while others had antibodies to two or fewer viruses. These results suggest that the mutations in the LRPPRC gene present in LSFC patients may affect the immune response to vaccines. Monitoring vaccine response in this fragile population should be considered to ensure full protection against pathogens

Effect of the LRPPRC A354V mutation on basal mitochondrial network morphology and functions.

<p>Representative live cell images of MTG-loaded control <b>(A)</b> and LSFC <b>(B)</b> fibroblasts used for quantitative analysis of mitochondrial network morphology. <b>(C)</b> Form Factor (FF) values calculated using the equation FF = 4π*Area/perimeter2 (n = 6). Representative live cell images of control <b>(D)</b> and LSFC <b>(E)</b> fibroblasts labeled with TMRE (red) and MTG (green). <b>(F)</b> Mitochondrial membrane (ΔΨ) potential expressed as the ratio of TMRE to MTG (n = 5). Lower values are indicative of reduced ΔΨ. <b>(G)</b> Mean fluorescence intensity of the mitochondria-specific superoxide probe MitoSOX in control and LSFC fibroblasts (n = 5). <b>(H)</b> Maximal ADP-driven respiration in digitonin-permeabilized fibroblasts energized with complex I (5 mM glutamate—2.5 mM malate; Glut-Mal; n = 15) or complex II substrates in presence of the complex I inhibitor rotenone (5 mM succinate + 1 μM rotenone; Succ+Rot; n = 14). Inset shows representative respirometry traces confirming that respiratory rates increased promptly in response to the addition of respiratory substrates, and were potently inhibited by complex I (rotenone), and complex II (malonate) blockers. <b>(I)</b> Mitochondrial calcium retention capacity (CRC) in control and LSFC fibroblasts exposed to progressive Ca2+ loading (n = 8). Inset shows representative Ca2+ kinetic tracings observed in control and LSFC fibroblasts. Tracings show progressive Ca2+ accumulation followed by PTP-induced release of accumulated Ca2+. Each spike indicates the addition of a calcium pulse of 83 nmoles. All experiments were performed in one control (EBS-4) and one LSFC (AL-006) cell line, except for the determination of ΔΨ, which was performed in EBS-3 and AL-002. Data are expressed as means ± S.E. Difference between control and LSFC cells was assessed with a paired t-test. Significantly different from the control group: * <i>p</i> < 0.05, ** <i>p</i> ≤ 0.01. Statistical power: C: 92%; F: 85%; G: 80%; H: Glut-Mal 80%; Succ+Rot: 96%; I: 73%.</p