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Advances in our understanding of human spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Qing Wen, Elizabeth I. Tang, Tito Jesus, Bruno Silvestrini, C. Yan Cheng
Studies using genetic models in mice have identified a number of genes associated with different cellular events during spermiogenesis.86 These include acrosome biogenesis (e.g., Gopc [Golgi-associated PDZ and coiled-coil motif containing protein] and Gba2 [ß glucosidase 2]), flagella assembly (e.g., Tekt2 [Tektin 2], Tek4 [Tektin 4], Vdac3 [voltage-dependent anion channel 3]), energy metabolism for motility (e.g., Catsper1-4 [cation channel, sperm associated 1, 2, 3, and 4], Gapdhs [glyceraldehyde-3-phospahte dehydrogenase sperm-specific]), nuclear condensation (e.g., Tnp1, [transition protein 1], Tnp2, Prm1 [protamine 1] Prm2), and cytoplasm removal (e.g., Spem 1 [sperm maturation 1]). In this context, it is of interest to note that early stages of spermiogenesis are monitored with various checkpoints, perhaps up to step 8 spermatids in rodents. For instance, round spermatids with defects are usually removed from the epithelium, such as through the formation of multinucleated spermatids—a common feature of abnormal spermiogenesis87 that leads to infertility. It appears that these multinucleated spermatid cells are formed, at least in part, as a result of defects in intercellular bridges, such as observed after colchicine treatment,88 which is known to induce microtubule disassembly.89 Also, deletion of genes important to early spermiogenesis, such as genes pertinent to acrosome biogenesis (e.g., Gopc), leads to infertility.90 However, a similar quality control mechanism is absent in late spermiogenesis because deletion of late spermatid-associated genes (e.g., Catsper1-4, Spem 1) in mice fail to affect testis weights, and sperm counts are normal and development of defective late spermatids continue to proceed to spermiation even though abnormal sperms are found in these mice.86 At least spermatids from these mice could be used for ICSI to obtain successful pregnancy;however, the biology of spermiogenesis in humans remains largely unexplored.
The relevant targets of anti-oxidative stress: a review
Published in Journal of Drug Targeting, 2021
The protective effect of ischaemic preconditioning on myocardium has been confirmed by a large number of experiments. Recent studies have shown that short-term myocardial ischemia-reperfusion can induce the up-regulation of many protective genes, such as antioxidant enzyme genes and NO synthase. Regulating the functional and metabolic changes of myocardium after ischemia-reperfusion is an important part of the myocardial endogenous protective mechanism, and it is also one of the important molecular bases for the myocardial protection of ischaemic preconditioning. Based on rat myocardial ischemia-reperfusion animal model, Jiang et al. screened the possible interaction proteins of MIP2 and identified voltage-dependent anion channel (VDAC), including VDAC1, VDAC2 and VDAC3 [120]. They found that VDAC1 might be a potential target for MIP2, and WD40 at the C-terminal of MIP2 is a domain that interacts with VDAC1. MIP2 can inhibit the reduction of mitochondrial membrane potential and cell death of cardiomyocytes induced by oxidative stress, and its mechanism may be related to the regulation of VDAC1.
Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Mohit M. Hulsurkar, Satadru K. Lahiri, Jason Karch, Meng C. Wang, Xander H.T. Wehrens
The role of mitochondrial dysfunction in cardiovascular diseases has been well studied and VDACs are implicated in pathological Ca2+ signaling within mitochondria [112–114]. VDACs are the most abundant proteins of the mitochondrial outer membrane and because of their location within the outer mitochondrial membrane, VDACs are the first regulators of Ca2+ uptake into the mitochondria [115]. When VDACs were discovered, they were called ‘mitochondrial porins,’ because they form a pore in the mitochondrial outer membrane. There are three isoforms of VDACs – VDAC1, VDAC2 and VDAC3, which are encoded by three individual nuclear genes [116,117]. VDAC1 is the most expressed isoform in the heart, followed by VDAC2 and VDAC3 [117,118]. As their name suggests, VDACs are dependent on voltage, and their conformation changes from a closed to open state with the change in action potential [119]. It has been widely accepted that VDACs are in an ‘open’ conformation at voltages from −40 mV to +40 mV [120]. However recently, it has been shown that VDAC3 does not share a similar voltage-dependency compared to VDAC1 and VDAC2 [121,122]. Therefore, VDAC3 could be a key regulator of Ca2+ uptake in mitochondria, particularly in pathological conditions when there is cytoplasmic Ca2+ overload [123]. Crystal structure of VDACs revealed that they have 19 β-sheets, forming a barrel-like structure across the mitochondrial outer membrane [124]. Since a critical function of VDACs is to transport small metabolites like ADP and ATP, the size of this pore is around 20 Å, around 8–10-fold larger than the size of Ca2+ ions [125]. Therefore, selective uptake of Ca2+ through VDACs is regulated through channel gating by changes in the VDAC structure [126]. Another critical factor regulating Ca2+ uptake by VDACs is their proximity to the SR [127]. VDACs are an integral part of the MAMs and are closely associated with the IP3R SR Ca2+ release channel [93]. This association allows VDACs to selectively and rapidly transport Ca2+ released from the SR through IP3Rs [128]. Therefore, IP3R inhibition could not only limit cytosolic Ca2+ levels, but it could also be an approach to reduce the pathological Ca2+ uptake into mitochondria. However, Dia et al [129]. showed that the loss of IP3R-VDAC mediated MAMs may play a role early in the progression of diabetic cardiomyopathy. Therefore, inhibition of this interaction needs to be carefully considered.