Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work‐up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence‐based recommendations have improved neonatal survival and short‐term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post‐translational short‐chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short‐chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

中文翻译：

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有机酸尿症：主要差距、新挑战和尚未实现的承诺

有机酸尿症 (OAD) 包括一组生化定义的遗传性代谢疾病。提高认识、可靠的诊断检查、针对某些 OAD 的新生儿筛查计划、优化新生儿和重症监护以及制定循证建议，提高了新生儿存活率和受影响个体的短期结果。然而，传统的治疗措施无法可靠地预防老年患者群体器官功能障碍的慢性进展。越来越多的证据表明，线粒体功能障碍可能最好地解释疾病进展。先前的研究表明，一些有毒代谢物靶向诱导协同生物能损伤的线粒体蛋白。尽管这些潜在的可逆机制有助于了解分解代谢状态下急性代谢失代偿的发展，但它们目前还不能完全解释疾病随年龄的进展。最近的研究将不平衡的自噬确定为甲基丙二酸尿症肾脏病理学中的一种新机制，导致细胞器的质量控制受损、线粒体老化以及随后的进行性器官功能障碍。此外，组蛋白和线粒体酶的翻译后短链赖氨酸酰化的发现有助于了解细胞内关键代谢物如何调节基因表达和酶功能。虽然酰化被认为是代谢适应的重要机制，从长远来看，遗传代谢疾病中短链赖氨酸酰化的潜在底物的慢性积累可能会产生相反的效果。最近，已在 1 型戊二酸尿症中证实了线粒体蛋白的戊二酰化模式改变。这些新见解可能弥合 OAD 自然史和病理生理学之间的差距，并且它们对开发靶向疗法的开发似乎很有希望。