The role of mitochondrial dynamics imbalance in hexavalent chromium-induced apoptosis and autophagy in rat testis

Chromium (Cr), a harmful heavy metal pollutant, is widely distributed in soil, water, and air [1]. Cr has many valence states, among which hexavalent chromium [Cr (VI)] is the most toxic [2]. Potassium dichromate (K2Cr2O7) is the main form of Cr (VI) [3], which endangers the animal's body organs. Animals can ingest through the skin, mucous membranes, and respiratory systems [4]. Cr (VI) has reproductive toxicity [5], which can cause the decline of the reproductive function of male animals and then cause severe economic losses [6]. The testes, as the reproductive organs of male animals, are vulnerable to environmental changes and easily damaged [7]. However, the mechanism of K2Cr2O7 toxicity to testis remains unknown.

Under normal circumstances, mitochondria maintain dynamic homeostasis through fission and fusion, enabling normal mitochondrial function [8]. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcription factor that regulates the expression of mitochondrial fission proteins and fusion proteins [9]. The Sirtuin 1 (Sirt1) is a highly conserved member of the Sirtuins family [10]. Sirt1 can deacetylate the downstream protein named PGC-1α, thereby increasing its activity [11]. Sirt1/PGC-1α is involved in regulating oxidative stress and improving mitochondrial oxidative metabolism, both of which are essential for maintaining cellular energy homeostasis [12]. The Sirt1/PGC-1α pathway may participate in mitochondrial dynamics imbalance leading to testicular damage.

Reactive oxygen species (ROS) are by-products of physiological and pathological cellular processes occurring in mitochondria [13]. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is an important transcription factor in the body, and its expression is controlled by Sirt1 [14]. Under abnormal conditions, the homeostasis of mitochondrial dynamics is impaired, which aggravates oxidative stress and increases ROS content. Normally, cells that activate the Sirt1/Nrf2 pathway counteract the adverse effects of ROS by regulating the expression of heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and superoxide dismutase (SOD) [15]. The Sirt1/Nrf2 pathway may be involved in maintaining constant mitochondrial dynamic homeostasis.

Mitochondria provide energy for spermatogenesis [16]. Beclin-1, autophagy-related 5 (ATG5), and autophagy-related 4B (ATG4B) are representatives of autophagy [17,18]. Disturbance of mitochondrial dynamics may be the critical mechanism of testicular injury, apoptosis, and autophagy.

This study aimed to determine the effect of Cr (VI) on the testis and explore potential signaling pathways related to dynamic mitochondrial homeostasis. Our study provides the scientific basis for reducing the harm of environmental Cr (VI) pollution to animal and human health.

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