Heterozygous disruption of ALAS1 in mice causes an accelerated age-dependent reduction in free heme, but not total heme, in skeletal muscle and liver
Citation:
Koen van Wijk, Takeru Akabane, Tomohiro Kimura, Shinichi Saitoh, Satoshi Okano, Vincent P. Kelly, Michiaki Takagi, Ken Kodama, Kiwamu Takahashi, Tohru Tanaka, Motowo Nakajima, Osamu Nakajima, Heterozygous disruption of ALAS1 in mice causes an accelerated age-dependent reduction in free heme, but not total heme, in skeletal muscle and liver, Archives of Biochemistry and Biophysics, 2021, 697, 108721Download Item:
Abstract:
5-Aminolevulinic acid (ALA) is the rate-limiting intermediate in heme biosynthesis in vertebrate species; a re-
action catalyzed by the mitochondrial ALA synthase 1 (ALAS1) enzyme. Previously we reported that knockdown
of the ubiquitously expressed ALAS1 gene in mice disrupts normal glucose metabolism, attenuates mitochondrial
function and results in a prediabetic like phenotype when animals pass 20-weeks of age (Saitoh et al., 2018).
Contrary to our expectations, the cytosolic and mitochondrial heme content of ALAS1 heterozygous (A1+/-)
mice were similar to WT animals. Therefore, we speculated that regulatory “free heme” may be reduced in an age
dependent manner in A1+/- mice, but not total heme.
Here, we examine free and total heme from the skeletal muscle and liver of WT and A1+/- mice using a
modified acetone extraction method and examine the effects of aging on free heme by comparing the amounts at
8–12 weeks and 30–36 weeks of age, in addition to the mRNA abundance of ALAS1. We found an age-dependent
reduction in free heme in the skeletal muscle and liver of A1+/- mice, while WT mice showed only a slight
decrease in the liver. Total heme levels showed no significant difference between young and aged WT and A1+/-
mice. ALAS1 mRNA levels showed an age-dependent reduction similar to that of free heme levels, indicating that
ALAS1 mRNA expression levels are a major determinant for free heme levels. The free heme pools in skeletal
muscle tissue were almost 2-fold larger than that of liver tissue, suggesting that the heme pool varies across
different tissue types. The expression of heme oxygenase 1 (HO-1) mRNA, which is expressed proportionally to the
amount of free heme, were similar to those of free heme levels. Taken together, this study demonstrates that the
free heme pool differs across tissues, and that an age-dependent reduction in free heme levels is accelerated in
mice heterozygous for ALAS1, which could account for the prediabetic phenotype and mitochondrial abnor-
mality observed in these animals.
Author's Homepage:
http://people.tcd.ie/kellyvpDescription:
PUBLISHED
Author: Kelly, Vincent
Type of material:
Journal ArticleCollections
Series/Report no:
Archives of Biochemistry and Biophysics;697;
Availability:
Full text availableKeywords:
prediabetic, Free heme, 5-Aminolevulinic acid (ALA), 5-Aminolevulinate synthase 1 (ALAS1), Aging, Skeletal muscle, LiverDOI:
https://doi.org/10.1016/j.abb.2020.108721Metadata
Show full item recordLicences: