Quantitative changes in Gimap3 and Gimap5 expression modify mitochondrial DNA segregation in mice. Genetics 2015 May;200(1):221-35
Date
03/27/2015Pubmed ID
25808953Pubmed Central ID
PMC4423365DOI
10.1534/genetics.115.175596Scopus ID
2-s2.0-84928987108 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Mammalian mitochondrial DNA (mtDNA) is a high-copy maternally inherited genome essential for aerobic energy metabolism. Mutations in mtDNA can lead to heteroplasmy, the co-occurence of two different mtDNA variants in the same cell, which can segregate in a tissue-specific manner affecting the onset and severity of mitochondrial dysfunction. To investigate mechanisms regulating mtDNA segregation we use a heteroplasmic mouse model with two polymorphic neutral mtDNA haplotypes (NZB and BALB) that displays tissue-specific and age-dependent selection for mtDNA haplotypes. In the hematopoietic compartment there is selection for the BALB mtDNA haplotype, a phenotype that can be modified by allelic variants of Gimap3. Gimap3 is a tail-anchored member of the GTPase of the immunity-associated protein (Gimap) family of protein scaffolds important for leukocyte development and survival. Here we show how the expression of two murine Gimap3 alleles from Mus musculus domesticus and M. m. castaneus differentially affect mtDNA segregation. The castaneus allele has incorporated a uORF (upstream open reading frame) in-frame with the Gimap3 mRNA that impairs translation and imparts a negative effect on the steady-state protein abundance. We found that quantitative changes in the expression of Gimap3 and the paralogue Gimap5, which encodes a lysosomal protein, affect mtDNA segregation in the mouse hematopoietic tissues. We also show that Gimap3 localizes to the endoplasmic reticulum and not mitochondria as previously reported. Collectively these data show that the abundance of protein scaffolds on the endoplasmic reticulum and lysosomes are important to the segregation of the mitochondrial genome in the mouse hematopoietic compartment.
Author List
Jokinen R, Lahtinen T, Marttinen P, Myöhänen M, Ruotsalainen P, Yeung N, Shvetsova A, Kastaniotis AJ, Hiltunen JK, Öhman T, Nyman TA, Weiler H, Battersby BJAuthor
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
3T3 CellsAlleles
Amino Acid Sequence
Animals
COS Cells
Cells, Cultured
DNA, Mitochondrial
Endoplasmic Reticulum
GTP Phosphohydrolases
GTP-Binding Proteins
Haplotypes
Lymphocytes
Lysosomes
Membrane Proteins
Mice
Mice, Inbred BALB C
Mitochondria
Molecular Sequence Data
Open Reading Frames
Protein Transport