Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice

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 Polg(D257A) mice. Plasma alanine increased markedly with t...

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Autores principales: Lim, Esther W., Handzlik, Michal K., Trefts, Elijah, Gengatharan, Jivani M., Pondevida, Carlos M., Shaw, Reuben J., Metallo, Christian M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519573/
https://www.ncbi.nlm.nih.gov/pubmed/34652935
http://dx.doi.org/10.1126/sciadv.abj4077
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author Lim, Esther W.
Handzlik, Michal K.
Trefts, Elijah
Gengatharan, Jivani M.
Pondevida, Carlos M.
Shaw, Reuben J.
Metallo, Christian M.
author_facet Lim, Esther W.
Handzlik, Michal K.
Trefts, Elijah
Gengatharan, Jivani M.
Pondevida, Carlos M.
Shaw, Reuben J.
Metallo, Christian M.
author_sort Lim, Esther W.
collection PubMed
description 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 Polg(D257A) 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 Polg(D257A) mice and subsequent hypoglycemia, which did not occur during normal mouse aging. Tracing with [(15)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, Polg(D257A) 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.
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spelling pubmed-85195732021-10-26 Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice Lim, Esther W. Handzlik, Michal K. Trefts, Elijah Gengatharan, Jivani M. Pondevida, Carlos M. Shaw, Reuben J. Metallo, Christian M. Sci Adv Biomedicine and Life Sciences 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 Polg(D257A) 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 Polg(D257A) mice and subsequent hypoglycemia, which did not occur during normal mouse aging. Tracing with [(15)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, Polg(D257A) 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. American Association for the Advancement of Science 2021-10-15 /pmc/articles/PMC8519573/ /pubmed/34652935 http://dx.doi.org/10.1126/sciadv.abj4077 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Lim, Esther W.
Handzlik, Michal K.
Trefts, Elijah
Gengatharan, Jivani M.
Pondevida, Carlos M.
Shaw, Reuben J.
Metallo, Christian M.
Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice
title Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice
title_full Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice
title_fullStr Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice
title_full_unstemmed Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice
title_short Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in Polg(D257A) mice
title_sort progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in polg(d257a) mice
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519573/
https://www.ncbi.nlm.nih.gov/pubmed/34652935
http://dx.doi.org/10.1126/sciadv.abj4077
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