Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing

Abstract

The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca2+ control; (d) disturbance to mitochondria–lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing

Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene

“…Evidence has also been found proving that a reduction in autophagy and mitophagy brings about acceleration of the aging process, while on the other hand the enhancement of these processes preserves cardiac homeostasis and extends the lifespan [ 39 ]. Our previous studies have demonstrated that overexpression of Cisd2 preserves cardiac mitochondrial function and reduces reactive oxygen species production, thus attenuating age-associated cardiac dysfunction [ 11 , 17 ]. The structure of mitochondria and the interactions that occur between mitochondria and other organelles are also well-preserved when there is an elevation of Cisd2 expression.…”

“…Interestingly, cardiomyocyte senescence can be alleviated by preventing mitochondrial dysfunction [ 7 , 8 ] or by the elimination of damaged cell components via upregulation of autophagy [ 9 , 10 ]. Mitochondrial damage is often found in aged hearts and this includes disorganized organelles, a loss of mitochondrial inner membrane cristae, and enlargement of the distance between the mitochondria and other organelles [ 11 ]. Age-related mitochondrial dysfunction is also evident in the aged heart at the functional level.…”

New Developments in Exosomal lncRNAs in Cardiovascular Diseases

“…Aging also mediates communication between cardiomyocytes and endothelial cells, fibroblasts, and immune cells ( 93 ) and promotes vascular wall endothelial damage, atherosclerosis, myocardial fibrosis, coronary heart disease, and heart failure ( 94 , 95 ). Currently, the strategies applied to delay cardiac aging include repairing mitochondrial dysfunction ( 96 ), targeting cardiac stem cell senescence and senescence-associated secretory phenotype changes ( 97 ), inducing autophagy ( 90 ), and hydrogen sulfide-mediated regulation of senescence signals ( 98 ). It has been reported that extracellular vesicles mediate cell senescence ( 99 ).…”

Cisd2 Protects the Liver from Oxidative Stress and Ameliorates Western Diet-Induced Nonalcoholic Fatty Liver Disease

“…Cisd2 deficiency causes a premature aging phenotype in Cisd2 knockout (Cisd2KO) mice. Conversely, a persistently high level of Cisd2 delays aging and mitigates age-related functional decline in multiple tissues, including skeletal muscle, neurons, skin, and heart [ 8 , 9 , 10 , 11 , 12 , 13 ]. In addition, Cisd2 has been detected to be associated with mitochondrial outer membranes, the ER, and mitochondria-associated ER membranes (MAMs) in various cell types.…”