Abstract:Aging is associated with structural and functional changes in the heart and is a major risk factor in developing cardiovascular disease. Many recent studies have focused on increasing our understanding of the basis of aging at the cellular and molecular levels in various tissues, including the heart. It is known that there is an age-related decline in cellular quality control pathways such as autophagy and mitophagy, which leads to accumulation of potentially harmful cellular components in cardiac myocytes. Th… Show more
“…In the last decade, several groups studied autophagy and mitophagy in aging and age-related diseases of different species such as flies, worms, humans, rats, and mice. Studies have also been done on rodent models of human disease and postmortem brains of healthy humans and humans with neurodegenerative disorders ( Palikaras et al, 2015 , 2018 ; Schiavi et al, 2015 ; Harper et al, 2018 ; Reddy et al, 2018 ; Manczak et al, 2018 ; Andreux et al, 2019 ; Castellazzi et al, 2019 ; Fang et al, 2019a , b ; Hou et al, 2019 ; Martín-Maestro et al, 2019 ; Reddy and Oliver, 2019 ; Oliver and Reddy, 2019a , b ; Wang et al, 2019 ; Li et al, 2020 ; Lou et al, 2020 ; Chen et al, 2020 ; Bakula and Scheibye-Knudsen, 2020 ; Liang and Gustafsson, 2020 ; Varghese et al, 2020 ; Luo et al, 2020 ; Markaki and Tavernarakis, 2020 ; Babbar et al, 2020 ; Aman et al, 2020 ; Cai and Jeong, 2020 ; Pakpian et al, 2020 ; Oh et al, 2020 ; Yang et al, 2020 ; Han et al, 2020 ; Pradeepkiran and Reddy, 2020 ). These articles (original and high impact review articles) have provided a large body of useful information about autophagy and mitophagy in different species of vertebrates and non-vertebrates.…”
Section: Age-related Factors In Defective Autophagymentioning
Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer’s disease (AD), Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.
“…In the last decade, several groups studied autophagy and mitophagy in aging and age-related diseases of different species such as flies, worms, humans, rats, and mice. Studies have also been done on rodent models of human disease and postmortem brains of healthy humans and humans with neurodegenerative disorders ( Palikaras et al, 2015 , 2018 ; Schiavi et al, 2015 ; Harper et al, 2018 ; Reddy et al, 2018 ; Manczak et al, 2018 ; Andreux et al, 2019 ; Castellazzi et al, 2019 ; Fang et al, 2019a , b ; Hou et al, 2019 ; Martín-Maestro et al, 2019 ; Reddy and Oliver, 2019 ; Oliver and Reddy, 2019a , b ; Wang et al, 2019 ; Li et al, 2020 ; Lou et al, 2020 ; Chen et al, 2020 ; Bakula and Scheibye-Knudsen, 2020 ; Liang and Gustafsson, 2020 ; Varghese et al, 2020 ; Luo et al, 2020 ; Markaki and Tavernarakis, 2020 ; Babbar et al, 2020 ; Aman et al, 2020 ; Cai and Jeong, 2020 ; Pakpian et al, 2020 ; Oh et al, 2020 ; Yang et al, 2020 ; Han et al, 2020 ; Pradeepkiran and Reddy, 2020 ). These articles (original and high impact review articles) have provided a large body of useful information about autophagy and mitophagy in different species of vertebrates and non-vertebrates.…”
Section: Age-related Factors In Defective Autophagymentioning
Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer’s disease (AD), Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.
“…In damaged mitochondria, the loss of membrane potential results in the accumulation of PINK1, the membrane depolarization sensor, on the outer mitochondrial membrane (OMM). PINK1 in turn recruits the E3 ubiquitin ligase Parkin, which functions as signal amplifier via ubiquitination of various OMM proteins, which in turn are recognized by p62/SQSTM1, a selective autophagy receptor, which function as adaptor protein to recruit autophagosome to the damaged mitochondria [ 74 ]. Fig.…”
Despite different phenotypic manifestations, mounting evidence points to similarities in the molecular basis of major neurodegenerative diseases (ND). CNS has evolved to be robust against hazard of ROS, a common perturbation aerobic organisms are confronted with. The trade-off of robustness is system's fragility against rare and unexpected perturbations. Identifying the points of CNS fragility is key for understanding etiology of ND. We postulated that the ‘primate differential redoxome’ (PDR), an assembly of proteins that contain cysteine residues present only in the primate orthologues of mammals, is likely to associate with an added level of regulatory functionalities that enhanced CNS robustness against ROS and facilitated evolution. The PDR contains multiple deterministic and susceptibility factors of major ND, which cluster to form coordinated redox networks regulating various cellular processes. The PDR analysis revealed a potential CNS fragility point, which appears to associates with a non-redundant PINK1-PRKN-SQSTM1(p62) axis coordinating protein homeostasis and mitophagy.
“…This pro-inflammatory environment may activate fibroblast proliferation and excessive production of extracellular matrix proteins which correlates with cardiomyopathies ( West et al, 2011 ; Lin and Kerkelä, 2020 ). These alterations at molecular levels are associated with cellular changes such as hypertrophy, fibrosis, accumulation of misfolded proteins, loss of cardiac cells, extracellular matrix remodeling and amyloid deposition and structural changes in the myocardium like left ventricle hypertrophy and left auricle hypertrophy, which causes diastolic dysfunction ( Steenman and Lande, 2017 ; Liang and Gustafsson, 2020 ). It has also been reported that mtDNA and whole mitochondria are released into bloodstream which offers a new biomarker of mitochondrial function and stress.…”
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.
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