Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation

Abstract

AimThoracic aortic aneurysms are a life-threatening condition often diagnosed too late. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms underlying aneurysm formation.Methods and resultsIn Fibulin-4R/R mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed proteomics and genomics studies on Fibulin-4R/R mouse aortas. Intriguingly, we observed alterations in mitochondrial protein composition in Fibulin-4R/R aortas. Consistently, functional studies in Fibulin-4R/R vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates. Yet, mitochondria in Fibulin-4R/R VSMCs showed no aberrant cytoplasmic localization. We found similar reduced mitochondrial respiration in Tgfbr-1M318R/+ VSMCs, a mouse model for Loeys-Dietz syndrome (LDS). Interestingly, also human fibroblasts from Marfan (FBN1) and LDS (TGFBR2 and SMAD3) patients showed lower oxygen consumption. While individual mitochondrial Complexes I–V activities were unaltered in Fibulin-4R/R heart and muscle, these tissues showed similar decreased oxygen consumption. Furthermore, aortas of aneurysmal Fibulin-4R/R mice displayed increased reactive oxygen species (ROS) levels. Consistent with these findings, gene expression analyses revealed dysregulation of metabolic pathways. Accordingly, blood ketone levels of Fibulin-4R/R mice were reduced and liver fatty acids were decreased, while liver glycogen was increased, indicating dysregulated metabolism at the organismal level. As predicted by gene expression analysis, the activity of PGC1α, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4R/R VSMCs. Increased TGFβ reduced PGC1α levels, indicating involvement of TGFβ signalling in PGC1α regulation. Activation of PGC1α restored the decreased oxygen consumption in Fibulin-4R/R VSMCs and improved their reduced growth potential, emphasizing the importance of this key regulator.ConclusionOur data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation.

Protection of hepatocyte mitochondrial function by blueberry juice and probiotics via SIRT1 regulation in non-alcoholic fatty liver disease

“…32 Decreased mitochondrial function and increased ROS are associated with the downregulation of PGC1A in Fibulin-4 mutant mice with aneurysmal aortas. 33 Melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission via the SIRT1-PGC1α pathway. 34 Our study showed that BP significantly increased the expression of PGC1α, while SIRT1 silencing reduced the PGC1α level and BP function, indicating that the effects of BP on mitochondria and oxidative stress might be mediated by SIRT1-mediated PGC1α regulation.…”

Mitochondrial function in thoracic aortic aneurysms

“… 7 van der Pluijm et al . 8 used proteomics, genomics, and functional experiments to study thoracic aortas of aneurysmal Fibulin-4R/R animals. Fibulin-4R/R mice showed alterations in protein composition affecting predominantly extracellular matrix (ECM) and cytoskeleton proteins, but also mitochondrial proteins and up-regulation of TGFβ1.…”

MiR‐144 protects the heart from hyperglycemia‐induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis

“…Mitochondrial biogenesis and function are typically tightly coupled in the heart . To determine whether mitochondrial biogenesis was impaired in hyperglycemic cardiomyocytes and, therefore, contributed to mitochondrial disorder, we assessed the expression of PGC‐1 α, which plays a critical role in controlling mitochondrial biogenesis and function in the heart under physiological or pathological conditions . Associated with the morphological defects observed in mitochondria, the mRNA expression levels of PGC‐1α, nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and other genes related to mitochondrial biogenesis decreased significantly in HG‐induced H9c2 cells (Figure F) and NRCM (Figure K).…”