Mitochondrial Remodeling and Dynamic Inter-Organellar Contacts in Cardiovascular Physiopathology

Editorial

30 April 2021

Editorial: Mitochondrial Remodeling and Dynamic Inter-Organellar Contacts in Cardiovascular Physiopathology

Gaetano Santulli

Giovanni Monaco

Valentina Parra

and

Giampaolo Morciano

2,421 views

7 citations

Editors

Giampaolo Morciano

University of Ferrara

Gaetano Santulli

Albert Einstein College of Medicine

Valentina María Parra

University of Chile

Giovanni Monaco

Centre for Drug Design and Discovery

Impact

Mitochondrial fusion and fission. Fusion of the mitochondrial outer membrane is carried out at MFN1 and 2, while L-OPA1 maintains continuity of the inner membrane, either by homotypic interaction or by binding cardiolipin (CL). YME1L constitutively cleaves L-OPA1, resulting in basal S-OPA1. Fission is mediated by recruitment of cytosolic DRP1 to the outer membrane using actin-dependent dynamics, where it is bound by mitochondrial binding partners FIS1, MFF, MiD49, and MiD51. When activated, OMA1 cleaves L-OPA1 to S-OPA1 in cooperation with YME1L for accumulation of fusion-inactive S-OPA1.

Review

25 March 2021

Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response

Robert Gilkerson

, 1 more and

Shaynah St. Vallier

Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨ_m) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨ_m is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1’s role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.

19,028 views

92 citations

Proposed Model of Cardiac Aging. The core of our model and the main driver of aging is mtDNA heteroplasmy. In aging, two vicious cycles were defined. Vicious cycle No1 will progressively increase the level of mtDNA heteroplasmy and decrease OXPHOS efficiency at the point to affect mitophagy and set the onset of Vicious cycle No2 that will progressively inhibit mitochondrial biogenesis and antioxidant response due to inhibition of PGC-1α and stimulation and upregulation of NCoR1. As a result, dysfunctional mitochondria will accumulate, increasing the number of mitoflashes and pathological ROS to finally trigger the mPTP opening and the release of DAMPs to initiate an inflammatory cell response and an apoptotic/necrotic stimulus. Furthermore, a metabolic switch from fatty acid oxidation to glucose oxidation will occur. Altogether, these events lead to cardiovascular diseases and cardiac failure. On the other hand, in young people, a low level of mtDNA heteroplasmy will keep the efficiency of the OXPHOS system which will maintain low NAD + /NADH and AMP/ATP ratios and a physiological amount of ROS. These conditions allow the Virtuous Cycle where MtDy will segregate dysfunctional mitochondrial units for degradation by mitophagy and will activate PGC-1α and NFE2L2 for mitochondrial biogenesis. Of note, cardiac cells are able to expel out mitochondria in vesicles called exospheres that are degraded by surrounding macrophages. In this model, we hypothesized that exosphere release, which is dependent on the autophagic machinery, is decreased in aging. Also, it is not clear yet whether in cardiac aging the protein MUL1 is involved in mitophagy, but it has been shown to be upregulated under cardiac damage. Along with NCoR1, another transcriptional corepressor like SMRT has been shown to be involved in aging.

Review

22 February 2021

mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology

Alvaro A. Elorza

and

Juan Pablo Soffia

The most common aging-associated diseases are cardiovascular diseases which affect 40% of elderly people. Elderly people are prone to suffer aging-associated diseases which are not only related to health and medical cost but also to labor, household productivity and mortality cost. Aging is becoming a world problem and it is estimated that 21.8% of global population will be older than 65 years old in 2050; and for the first time in human history, there will be more elderly people than children. It is well accepted that the origin of aging-associated cardiovascular diseases is mitochondrial dysfunction. Mitochondria have their own genome (mtDNA) that is circular, double-stranded, and 16,569 bp long in humans. There are between 500 to 6000 mtDNA copies per cell which are tissue-specific. As a by-product of ATP production, reactive oxygen species (ROS) are generated which damage proteins, lipids, and mtDNA. ROS-mutated mtDNA co-existing with wild type mtDNA is called mtDNA heteroplasmy. The progressive increase in mtDNA heteroplasmy causes progressive mitochondrial dysfunction leading to a loss in their bioenergetic capacity, disruption in the balance of mitochondrial fusion and fission events (mitochondrial dynamics, MtDy) and decreased mitophagy. This failure in mitochondrial physiology leads to the accumulation of depolarized and ROS-generating mitochondria. Thus, besides attenuated ATP production, dysfunctional mitochondria interfere with proper cellular metabolism and signaling pathways in cardiac cells, contributing to the development of aging-associated cardiovascular diseases. In this context, there is a growing interest to enhance mitochondrial function by decreasing mtDNA heteroplasmy. Reduction in mtDNA heteroplasmy is associated with increased mitophagy, proper MtDy balance and mitochondrial biogenesis; and those processes can delay the onset or progression of cardiovascular diseases. This has led to the development of mitochondrial therapies based on the application of nutritional, pharmacological and genetic treatments. Those seeking to have a positive impact on mtDNA integrity, mitochondrial biogenesis, dynamics and mitophagy in old and sick hearts. This review covers the current knowledge of mitochondrial physiopathology in aging, how disruption of OXPHOS or mitochondrial life cycle alter mtDNA and cardiac cell function; and novel mitochondrial therapies to protect and rescue our heart from cardiovascular diseases.

13,314 views

39 citations

Pathological stress including hypertension, ischemia/reperfusion, and diabetes mellitus results in dysfunctional mitochondria. Various cardiovascular risk factors including hypertension, ischemia/reperfusion injury, and diabetes leads to mitochondrial dysfunction. Without adequate quality control of the damaged mitochondria, this may result in (1) ATP depletion, (2) overproduction of ROS/RNS, (3) mitochondria-dependent cell death (apoptosis), and (4) systemic inflammation which provokes cardiovascular pathogenesis.

Review

22 March 2021

Quality Matters? The Involvement of Mitochondrial Quality Control in Cardiovascular Disease

Kai-Lieh Lin

, 6 more and

Tsu-Kung Lin

9,813 views

24 citations

Estrogen and testosterone influence mitochondrial dynamics and cross talk between organelles. Estrogen, via PPARα, upregulates PGC-1α to initiate transcription of mitochondrial dynamic proteins and induce peroxisomal biogenesis. Testosterone upregulates PGC-1α, via AMPK, to influence mitochondrial dynamics. Both sex hormones increase antioxidant proteins to mitigate damaging reactive oxygen species, regulate Ca2+ signaling via K+ATP channels on the sarcoplasmic reticulum, and prevent various forms of cell death in CVD including apoptosis, necrosis, and mitophagy.

Mini Review

11 February 2021

Sex Hormone Regulation of Proteins Modulating Mitochondrial Metabolism, Dynamics and Inter-Organellar Cross Talk in Cardiovascular Disease

Shannon Lynch

, 2 more and

Samantha Giordano-Mooga

6,041 views

20 citations

$Mitochondria-SR-T tubule communication in arrhythmogenesis. Conditions that favor Ca2+ overload, such as chronic adrenergic stimulation, cause the following: (1) increased Ca2+ transport through the mCU to the mitochondrial matrix, shortening mitochondrial Ca2+ transients’ amplitude and stabilizing the mitochondrial Ca2+ concentration at a high level, which causes mitochondrial Ca2+ overload; (2) increased ROS production by mitochondrial structures, such as the ETC, with subsequent (3) loss of ΔΨm and (4) decreased ATP production; (5) opening of the mPTP, which initializes the cell death signal; (6) increased mCU activity by oxidation and, possibly, AMPK phosphorylation following a decline in the ATP concentration, which increases Ca2+ transport and ROS production; (7) decreased SERCA activity by oxidation and decreased PLB phosphorylation, which (8) increases the diastolic Ca2+ level and (9) decreases SR Ca2+ content, reducing contractility; (10) increased CAMKII activity by Ca2+ activation, oxidation, and autophosphorylation; (11) sensibilization of the RyR2 to luminal Ca2+ content with a reduced refractory state by oxidation and CAMKII hyperphosphorylation, with a subsequent unbinding of its modulating protein, calstabin2, and lower sensitivity to cytosolic Ca2+ by Mg2+ binding; (12) oxidation of LTCCs, which increases the amount of Ca2+ entering the cardiomyocyte upon activation; (13) opening of sarcKATP channels due to a reduced ATP/ADP ratio, which decreases the cardiomyocyte’s bathmotropism and dromotropism; (14) increased activity of the NCX, which slowly depolarizes the cardiomyocyte and increases the risk of an unsolicited AP; (15) connexin 43 (Cx43) translocation in certain cardiac pathologies or pannexin 1 (Panx1) opening with Ca2+ or ROS transports ATP into the extracellular matrix, where it is transformed into adenosine, and both ATP and adenosine cause TGF-β1 expression and fibrosis. All these changes combined produce, at the cellular level, Ca2+ mishandling with subsequent low contractility and spontaneous contraction that can propagate to neighboring cardiomyocytes and, at the tissular level, patches of slow conduction by reduced dromotropism or collagen deposition caused by cardiomyocyte cell death and fibrosis, which enable possible re-entry zones for sustained arrhythmias.$

Review

28 January 2021

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

Felipe Salazar-Ramírez

, 1 more and

Gerardo García-Rivas

4,864 views

14 citations

Original Research

25 January 2021

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Claire Angebault

, 4 more and

Jérémy Fauconnier

5,888 views

34 citations

Review

12 January 2021

Mitochondrial Function and Dysfunction in Dilated Cardiomyopathy

Daniela Ramaccini

, 9 more and

Michelle L. Matter

Mitochondrial functions. Left panel: under physiological conditions, mitochondria functions are the core of bioenergetics activities, providing ATP throughout the OXPHOS, which is also an important source of ROS. Basal ROS levels are maintained by the radical scavenging network. Additionally, mitochondria are calcium-buffering organelles. Ca2+ homeostasis is finely controlled by its uptake through voltage-dependent anion-selective channel proteins (VDACs) and the mitochondrial Ca2+ uniporter (MCU) complex, Ca2+ efflux is controlled by NCLX. Right top panel: pathological conditions, ROS burst and mitochondrial Ca2+ overload activate regulated cell death (RCD) inducing either apoptosis or necrosis pathway through the PTPC opening. Right-bottom panel: Ca2+ uptake activates mitochondrial metabolism. Fatty acids are metabolized via FAO toward the TCA cycle providing energy as FADH2 and NADPH are building blocks for biosynthesis. Voltage-dependent anion-selective channel proteins (VDAC), Mitochondrial Calcium Uniporter Complex (MCUC), Mitochondrial Na+/Ca2+ exchanger (NCLX), oxidative phosphorylation (OXPHOS), Permeability transition pore complex (PTPC), ADP/ATP translocase (ANT) and peptidyl-prolyl cis-trans isomerase Cyclophilin D (CypD), cytochrome C (cyt C), adenosine triphosphate (ATP), reactive oxygen species (ROS), tricarboxylic acid cycle (TCA), fatty acid oxidation (FAO), α -ketoglutarate dehydrogenase (α-KG), oxaloacetate (OAA), Acetyl coenzyme A (Acetyl CoA) mitochondrial membrane potential (Δψm) (Created with BioRender.com).

Cardiac tissue requires a persistent production of energy in order to exert its pumping function. Therefore, the maintenance of this function relies on mitochondria that represent the “powerhouse” of all cardiac activities. Mitochondria being one of the key players for the proper functioning of the mammalian heart suggests continual regulation and organization. Mitochondria adapt to cellular energy demands via fusion-fission events and, as a proof-reading ability, undergo mitophagy in cases of abnormalities. Ca²⁺ fluxes play a pivotal role in regulating all mitochondrial functions, including ATP production, metabolism, oxidative stress balance and apoptosis. Communication between mitochondria and others organelles, especially the sarcoplasmic reticulum is required for optimal function. Consequently, abnormal mitochondrial activity results in decreased energy production leading to pathological conditions. In this review, we will describe how mitochondrial function or dysfunction impacts cardiac activities and the development of dilated cardiomyopathy.

30,245 views

93 citations