Imaging Mitochondrial Dynamics in the Adult Heart

Background Mitochondrial dynamics, the phenomenon which incorporates inter-mitochondrial communication and changes in mitochondrial morphology is central to cellular homeostasis. Although the phenomenon of mitochondrial dynamics has been comprehensively studied under normal and pathological conditions in non-cardiac cells, and more recently in cardiac cell lines, its relevance to adult cardiomyocytes has not been so well-established and is investigated in this thesis. Methods and Results Using 2D and 3D electron microscopy, we initially evaluated the morphological features of the 3 different mitochondrial subpopulations (interfibrillar, peri-nuclear, subsarcolemmal) in adult rodent cardiomyocytes, and demonstrated that they are morphologically unique. These morphological characteristics were found to be altered under pathological conditions such as ischaemia or the genetic ablation of mitochondrial fusion proteins “mitofusins”. Using mice expressing the Dendra2 fluorescence probe, we then confirmed that mitochondrial fusion events (“the inter-mitochondrial communication”) occur in live adult cardiomyocytes, and the fusion rates differ according to the mitochondrial subpopulation. We next performed high throughput screening of a small molecule library and identified hydralazine (a drug used to treat hypertension and heart failure) to be a novel modulator of mitochondrial dynamics, acting to inhibit mitochondrial fission and protect against the detrimental effects of acute myocardial ischaemia/reperfusion injury by preserving mitochondrial dynamics. Conclusion This thesis has demonstrated that 2D and 3D changes in mitochondrial shape features, as well as alterations in inter-mitochondrial communication, are of high relevance to adult rodent cardiomyocytes. Hydralazine-induced cardioprotection in the setting of IRI demonstrates the significance of distinct aspects of mitochondrial dynamics and reveals the role they play in the normal functioning of adult cardiomyocytes

The RISK pathway leading to mitochondria and cardioprotection: how everything started

Ischaemic heart disease, which often manifests clinically as myocardial infarction (MI), remains a major cause of mortality worldwide. Despite the development of effective pre-clinical cardioprotective therapies, clinical translation has been disappointing. Nevertheless, the 'reperfusion injury salvage kinase' (RISK) pathway appears to be a promising target for cardioprotection. This pathway is crucial for the induction of cardioprotection by numerous pharmacological and non-pharmacological interventions, such as ischaemic conditioning. An important component of the cardioprotective effects of the RISK pathway involves the prevention of mitochondrial permeability transition pore (MPTP) opening and subsequent cardiac cell death. Here, we will review the historical perspective of the RISK pathway and focus on its interaction with mitochondria in the setting of cardioprotection

Assessing the effects of mitofusin 2 deficiency in the adult heart using 3D electron tomography

The effects of mitofusin 2 (MFN2) deficiency, on mitochondrial morphology and the mitochondria-junctional sarcoplasmic reticulum (jSR) complex in the adult heart, have been previously investigated using 2D electron microscopy, an approach which is unable to provide a 3D spatial assessment of these imaging parameters. Here, we use 3D electron tomography to show that MFN2-deficient mitochondria are larger in volume, more elongated, and less rounded; have fewer mitochondria-jSR contacts, and an increase in the distance between mitochondria and jSR, when compared to WT mitochondria. In comparison to 2D electron microscopy, 3D electron tomography can provide further insights into mitochondrial morphology and the mitochondria-jSR complex in the adult heart

From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on "New frontiers in cardiovascular research"

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome

Oestrogenic Regulation of Mitochondrial Dynamics

Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion–fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems

Oestrogenic Regulation of Mitochondrial Dynamics

Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This work was supported by a grant from the European Union (101024324).Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion–fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.Peer reviewe

Erratum : Correction: Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction (Cell death & disease (2016) 7 (e2238))

The original version of this article unfortunately contained a mistake in an author name. The correct author name is GW Dorn 2nd. The original article has been corrected

Correction to: RIC in COVID-19—a Clinical Trial to Investigate Whether Remote Ischemic Conditioning (RIC) Can Prevent Deterioration to Critical Care in Patients with COVID-19 : RIC in COVID-19—a Clinical Trial to Investigate Whether Remote Ischemic Conditioning (RIC) Can Prevent Deterioration to Critical Care in Patients with COVID-19 (Cardiovascular Drugs and Therapy, (2021), 10.1007/s10557-021-07221-y)

Publisher Copyright: © 2021, Springer Science+Business Media, LLC, part of Springer Nature.The original article has been corrected. Author “Dereks M. Yellon” should be “Derek M. Yellon.”

RIC in COVID-19—a Clinical Trial to Investigate Whether Remote Ischemic Conditioning (RIC) Can Prevent Deterioration to Critical Care in Patients with COVID-19

Funding for this study was provided by grants from the Thompson Family Trust, The Hatter Cardiovascular Institute, Mancherje-Potash Foundation, and the Fundação de Apoio a Pesquisa do Estado de São Paulo (FAPESP). Publisher Copyright: © 2021, The Author(s).Purpose: Coronavirus disease 19 (COVID-19) has, to date, been diagnosed in over 130 million persons worldwide and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several variants of concern have emerged including those in the United Kingdom, South Africa, and Brazil. SARS-CoV-2 can cause a dysregulated inflammatory response known as a cytokine storm, which can progress rapidly to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Suppressing these cytokine elevations may be key to improving outcomes. Remote ischemic conditioning (RIC) is a simple, non-invasive procedure whereby a blood pressure cuff is inflated and deflated on the upper arm for several cycles. “RIC in COVID-19” is a pilot, multi-center, randomized clinical trial, designed to ascertain whether RIC suppresses inflammatory cytokine production. Methods: A minimum of 55 adult patients with diagnosed COVID-19, but not of critical status, will be enrolled from centers in the United Kingdom, Brazil, and South Africa. RIC will be administered daily for up to 15 days. The primary outcome is the level of inflammatory cytokines that are involved in the cytokine storm that can occur following SARS-CoV-2 infection. The secondary endpoint is the time between admission and until intensive care admission or death. The in vitro cytotoxicity of patient blood will also be assessed using primary human cardiac endothelial cells. Conclusions: The results of this pilot study will provide initial evidence on the ability of RIC to suppress the production of inflammatory cytokines in the setting of COVID-19. Trial Registration: NCT04699227, registered January 7th, 2021.Peer reviewe