Neuhaus Johannes Friedrich Georg, Baris Olivier Richard, Kittelmann Anne, Becker Katrin, Rothschild Markus Alexander, Wiesner Rudolf Josef
Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany.
Neuroendocrinology. 2017;104(1):72-84. doi: 10.1159/000444680. Epub 2016 Feb 20.
Aging is a multifactorial process characterized by organ loss of function and degeneration, but the mechanisms involved remain elusive. We have shown recently that catecholamine metabolism drives the accumulation of mitochondrial DNA (mtDNA) deletions in dopaminergic cells, which likely contribute to their degeneration during aging. Here we investigated whether the well-documented degeneration and altered function of adrenals during aging is linked to catecholamine production in the medulla followed by accumulation of mtDNA deletions.
We analyzed adrenal medullary and cortical samples of both murine and human origin covering a wide range of ages for mtDNA deletion content, mtDNA copy number, mitochondrial and cellular integrity as well as aging-related tissue changes such as fibrosis.
Indeed, we demonstrate in mice and humans that the adrenal medulla accumulates a strikingly high amount of mtDNA deletions with age, causing mitochondrial dysfunction in the adrenal medulla, but also in the cortex, accompanied by apoptosis and, more importantly, by severe inflammation and remarkable fibrosis. Additionally, a concomitant and dramatic loss of medullary and cortical cells is observed in old animals.
Our results show that accumulation of mtDNA deletions, and the ensuing mitochondrial dysfunction, is a hallmark of adrenal aging, further strengthening the hypothesis that catecholamine metabolism is detrimental to mtDNA integrity, mitochondrial function and cell survival. Moreover, the cell loss potentially induced by mitochondrial dysfunction could explain the decline in adrenal hormonal and steroidal secretion during aging.
衰老为多因素过程，其特征为器官功能丧失与退化，但其中涉及的机制仍不清楚。我们最近发现，儿茶酚胺代谢促使多巴胺能细胞中线粒体DNA（mtDNA）缺失的积累，这可能导致其在衰老过程中退化。在此，我们研究了衰老过程中肾上腺的退化和功能改变是否与髓质中儿茶酚胺的产生以及随后mtDNA缺失的积累有关。
我们分析了涵盖广泛年龄范围的小鼠和人类肾上腺髓质和皮质样本，以检测mtDNA缺失含量、mtDNA拷贝数、线粒体和细胞完整性以及与衰老相关的组织变化，如纤维化。
实际上，我们在小鼠和人类中均证明，随着年龄增长，肾上腺髓质积累了惊人数量的mtDNA缺失，这不仅导致肾上腺髓质线粒体功能障碍，也导致皮质线粒体功能障碍，同时伴有细胞凋亡，更重要的是，伴有严重炎症和显著纤维化。此外，在老年动物中观察到髓质和皮质细胞同时大量丢失。
我们的结果表明，mtDNA缺失的积累以及随之而来的线粒体功能障碍是肾上腺衰老的标志，进一步强化了儿茶酚胺代谢对mtDNA完整性、线粒体功能和细胞存活有害的假说。此外，线粒体功能障碍可能诱导的细胞丢失可以解释衰老过程中肾上腺激素和甾体分泌的下降。
