Lim Esther W, Handzlik Michal K, Trefts Elijah, Gengatharan Jivani M, Pondevida Carlos M, Shaw Reuben J, Metallo Christian M
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA.
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
Sci Adv. 2021 Oct 15;7(42):eabj4077. doi: 10.1126/sciadv.abj4077.
Mitochondria are central to metabolic homeostasis, and progressive mitochondrial defects have diverse metabolic consequences that could drive distinct pathophysiological states. Here, we comprehensively characterized metabolic alterations in mice. Plasma alanine increased markedly with time, with other organic acids accumulating to a lesser extent. These changes were reflective of increased Cori and Cahill cycling in mice and subsequent hypoglycemia, which did not occur during normal mouse aging. Tracing with [N]ammonium further supported this shift in amino acid metabolism with mild impairment of the urea cycle. We also measured alterations in the lipidome, observing a reduction in canonical lipids and accumulation of 1-deoxysphingolipids, which are synthesized from alanine via promiscuous serine palmitoyltransferase activity and correlate with peripheral neuropathy. Consistent with this metabolic link, mice exhibited thermal hypoalgesia. These results highlight the longitudinal changes that occur in intermediary metabolism upon mitochondrial impairment and identify a contributing mechanism to mitochondria-associated neuropathy.
线粒体对于代谢稳态至关重要，而渐进性线粒体缺陷会产生多种代谢后果，可能导致不同的病理生理状态。在此，我们全面表征了小鼠的代谢改变。血浆丙氨酸随时间显著增加，其他有机酸积累程度较低。这些变化反映了小鼠体内科里循环和卡希尔循环增加以及随后的低血糖，而这在正常小鼠衰老过程中并未发生。用[氮]铵追踪进一步支持了氨基酸代谢的这种转变以及尿素循环的轻度受损。我们还测量了脂质组的变化，观察到经典脂质减少以及1-脱氧鞘脂积累，1-脱氧鞘脂是通过混杂的丝氨酸棕榈酰转移酶活性由丙氨酸合成的，并且与周围神经病变相关。与这种代谢联系一致，小鼠表现出热痛觉减退。这些结果突出了线粒体损伤后中间代谢中发生的纵向变化，并确定了线粒体相关神经病变的一个促成机制。
