Mitochondrial mechanosensor in cardiovascular diseases

Malvezzi, Cristina Caffarra; Cabassi, Aderville; Miragoli, Michele

doi:10.1530/vb-20-0002

Cited by 7 publications

(3 citation statements)

References 60 publications

(81 reference statements)

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“…The interaction between mitochondria and sarcomere directly affects cardiomyocyte excitation‐contraction and is also involved in mechano‐transduction through the cytoskeletal proteins and the sarcoplasmic reticulum. Mitochondria adapt their structure and activity by sensing mechanical forces in the environment and, within a dynamic organ such as the heart, it contributes to calcium homeostasis 55 . Taken together, these results suggest that Opa1 deficiency affects in vivo response to high blood pressure via the induction of an excessive oxidative stress probably due to an altered mitochondrial function demonstrated by a hyper‐fragmentation of the mitochondria.…”

Section: Discussionmentioning

confidence: 81%

Protective role of the mitochondrial fusion protein OPA1 in hypertension

et al. 2021

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Hypertension is associated with excessive reactive oxygen species (ROS) production in vascular cells. Mitochondria undergo fusion and fission, a process playing a role in mitochondrial function. OPA1 is essential for mitochondrial fusion. Loss of OPA1 is associated with ROS production and cell dysfunction. We hypothesized that mitochondria fusion could reduce oxidative stress that defect in fusion would exacerbate hypertension. Using (a) Opa1 haploinsufficiency in isolated resistance arteries from Opa1+/− mice, (b) primary vascular cells from Opa1+/− mice, and (c) RNA interference experiments with siRNA against Opa1 in vascular cells, we investigated the role of mitochondria fusion in hypertension. In hypertension, Opa1 haploinsufficiency induced altered mitochondrial cristae structure both in vascular smooth muscle and endothelial cells but did not modify protein level of long and short forms of OPA1. In addition, we demonstrated an increase of mitochondrial ROS production, associated with a decrease of superoxide dismutase 1 protein expression. We also observed an increase of apoptosis in vascular cells and a decreased VSMCs proliferation. Blood pressure, vascular contractility, as well as endothelium‐dependent and ‐independent relaxation were similar in Opa1+/−, WT, L‐NAME‐treated Opa1+/− and WT mice. Nevertheless, chronic NO‐synthase inhibition with L‐NAME induced a greater hypertension in Opa1+/− than in WT mice without compensatory arterial wall hypertrophy. This was associated with a stronger reduction in endothelium‐dependent relaxation due to excessive ROS production. Our results highlight the protective role of mitochondria fusion in the vasculature during hypertension by limiting mitochondria ROS production.

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Section: Discussionmentioning

confidence: 81%

Protective role of the mitochondrial fusion protein OPA1 in hypertension

et al. 2021

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“…Metabolic changes, including mitochondrial ETC function, morphology, and ROS production, are guided by mechanical stress. CM hypertrophy is also a key parameter of maturation post-natally (Caffarra Malvezzi et al, 2020 ). Inert polycaprolactone (PCL) planar layers with different cross-linking densities and Young modulus ranging from 1 to 133 MPa (measured by tensile test) have been prepared (Govoni et al, 2013 ).…”

Section: Biological Function Of Mechanical Stress In Cmsmentioning

confidence: 99%

“…In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival (Kaasik et al, 2004 ; Brown et al, 2010 ; Caffarra Malvezzi et al, 2020 ; Lyra-Leite et al, 2020 ). Within CMs, mitochondria are one of the most important organelles.…”

Section: Introductionmentioning

confidence: 99%

Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes

Liao

Yan

et al. 2021

Front. Cell Dev. Biol.

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Mitochondria are one of the most important organelles in cardiomyocytes. Mitochondrial homeostasis is necessary for the maintenance of normal heart function. Mitochondria perform four major biological processes in cardiomyocytes: mitochondrial dynamics, metabolic regulation, Ca2+ handling, and redox generation. Additionally, the cardiovascular system is quite sensitive in responding to changes in mechanical stress from internal and external environments. Several mechanotransduction pathways are involved in regulating the physiological and pathophysiological status of cardiomyocytes. Typically, the extracellular matrix generates a stress-loading gradient, which can be sensed by sensors located in cellular membranes, including biophysical and biochemical sensors. In subsequent stages, stress stimulation would regulate the transcription of mitochondrial related genes through intracellular transduction pathways. Emerging evidence reveals that mechanotransduction pathways have greatly impacted the regulation of mitochondrial homeostasis. Excessive mechanical stress loading contributes to impairing mitochondrial function, leading to cardiac disorder. Therefore, the concept of restoring mitochondrial function by shutting down the excessive mechanotransduction pathways is a promising therapeutic strategy for cardiovascular diseases. Recently, viral and non-viral protocols have shown potentials in application of gene therapy. This review examines the biological process of mechanotransduction pathways in regulating mitochondrial function in response to mechanical stress during the development of cardiomyopathy and heart failure. We also summarize gene therapy delivery protocols to explore treatments based on mechanical stress–induced mitochondrial dysfunction, to provide new integrative insights into cardiovascular diseases.

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