Cisd2 is essential to delaying cardiac aging and to maintaining heart functions

Abstract

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart’s electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction.

An Examination of Lactobacillus paracasei GKS6 and Bifidobacterium lactis GKK2 Isolated from Infant Feces in an Aged Mouse Model

“…A persistent level of Cisd2 protected mitochondrial dysregulation and reduced DNA damage caused by oxidative stress; in addition, Cisd2 was involved in calcium homeostasis through the regulation of the calcium channels located on the endoplasmic reticulum and mitochondrial outer membranes [28][29][30]. ese affections maintain a better physical function in skeletal muscle, liver, and heart [31,32]. e Cisd2 mKO mice showed a similar pattern as naturally aged mice in the decline of gastrocnemius muscle [33].…”

Exercise and the Cisd2 Prolongevity Gene: Two Promising Strategies to Delay the Aging of Skeletal Muscle

“…Cisd2 loss-of-function mice exhibit premature aging phenotypes and have a shortened lifespan. Conversely, Cisd2 transgenic mice not only are longer lived (both males and females), they also have a healthier physical condition, such as better fur function, increased muscle strength and improved cardiac function [75,76]. The Cisd2 protein has been localized to mitochondria, mitochondria-associated membrane (MAM) and the endoplasmic reticulum (ER), and is involved in calcium homeostasis [77].…”

“…The Cisd2 protein has been localized to mitochondria, mitochondria-associated membrane (MAM) and the endoplasmic reticulum (ER), and is involved in calcium homeostasis [77]. We have demonstrated using aged mice that maintenance of the expression level of Cisd2 sustains metabolic activity, ameliorates aging-associated mitochondrial dysregulation, reduces DNA damages and improves the calcium imbalance within skeletal muscles [75], liver [77] and heart [76]. Taken together, Cisd2 is a lifespan regulator and its expression level seems to be a critical factor in relation to prolong healthspan.…”

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.…”

“…ER and mitochondria are the two major intracellular Ca 2+ stores that respond to the signals for Ca 2+ mobilization, while MAMs serve as hotspots for Ca 2+ transfer between the ER and mitochondria. Studies from our group and other laboratories have revealed that Cisd2 plays an essential role in mitochondrial integrity and intracellular Ca 2+ homeostasis [ 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Furthermore, Cisd2 deficiency leads to mitochondrial dysfunction and structural breakdown [ 13 ].…”