Nrf2 Deficiency Attenuates Testosterone Efficiency in Ameliorating Mitochondrial Function of the Substantia Nigra in Aged Male Mice.

Yu Wang,Rui Cui,Qiqing Guo,Guoliang Zhang,Yunxiao Kang,Tianyun Zhang,Xiaoming Ji,Jing Che,Geming Shi,Baoliang Ren,Claudio Cabello-Verrugio

doi:10.1155/2022/3644318

Abstract

Reduced testosterone level is a common feature of aging in men. Aging, as a risk factor for several neurodegenerative disorders, shows declined mitochondrial function and downregulated mitochondrial biogenesis and mitochondrial dynamics. Mitochondrial biogenesis and mitochondrial dynamics are crucial in maintaining proper mitochondrial function. Supplementation with testosterone is conducive to improving mitochondrial function of males during aging. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of redox homeostasis, is involved in the ameliorative effects of testosterone supplementation upon aging. To explore Nrf2 role in the effects of testosterone supplementation on mitochondrial function during aging, we studied the efficiency of testosterone supplementation in improving mitochondrial function of Nrf2 knockout- (KO-) aged male mice by analyzing the changes of mitochondrial biogenesis and mitochondrial dynamics. It was found that wild-type- (WT-) aged male mice showed low mitochondrial function and expression levels of PGC-1α, NRF-1\\NRF-2, and TFAM regulating mitochondrial biogenesis, as well as Drp1, Mfn1, and OPA1 controlling mitochondrial dynamics in the substantia nigra (SN). Nrf2 KO aggravated the defects above in SN of aged male mice. Testosterone supplementation to WT-aged male mice significantly ameliorated mitochondrial function and upregulated mitochondrial biogenesis and mitochondrial dynamics, which were not shown in Nrf2 KO-aged male mice due to Nrf2 deficiency. Testosterone deficiency by gonadectomy (GDX) decreased mitochondrial function, downregulated mitochondrial biogenesis, and altered mitochondrial dynamics balance in young male mice. Supplementation with testosterone to Nrf2 KO-GDX mice only ameliorated the alterations above but did not reverse them to sham level. Nrf2 deficiency attenuated testosterone efficiency in ameliorating mitochondrial function in the SN of aged male mice through mitochondrial biogenesis and mitochondrial dynamics to some extent. Activation of Nrf2 might contribute to testosterone-upregulating mitochondrial biogenesis and mitochondrial dynamics in the SN during aging to produce efficient mitochondria for ATP production.

Highlights

Aging, as a risk factor for several neurodegenerative disorders including Parkinson’s disease (PD) and Alzheimer’s disease, shows mild to severe mitochondrial dysfunction
Based on the decreased mitochondrial biogenesis signaling in aging process, the improved mitochondrial function in aging via the induction of mitochondrial biogenesis [30], and the above-found effects of Nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency on mitochondrial function of aged male mice during TP supplementation, we examined the altered expression of key inducer and effectors of mitochondrial biogenesis, namely, PGC-1α, nuclear respiratory factor 1 (NRF-1), NRF-2, and TFAM in the substantia nigra (SN) of experimental mice
Since stimulation of mitochondrial biogenesis is accompanied by increased mitochondrial content, so following, we investigated the effects of Nrf2 deficiency on mitochondrial content in the SN of aged mice supplemented with TP through detecting citrate synthase (CS) activity, Mitochondrial DNA (mtDNA) copy number, and mitochondrial number

Summary

Introduction

As a risk factor for several neurodegenerative disorders including Parkinson’s disease (PD) and Alzheimer’s disease, shows mild to severe mitochondrial dysfunction. Mitochondrial dysfunction, such as the decreased oxidative phosphorylation, the increased reactive oxygen species (ROS), and oxidative damage, is found in aged subjects and subjects with aging-related neurodegeneration [1]. The reduction of oxidative damage to mitochondria by enhancing antioxidative capability and the preservation of the normal mitochondrial function via regulating mitochondrial biogenesis or mitochondrial dynamics have been proposed as strategies to mitigate aging and aging-related neurodegenerative disease [3, 5]

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