Heteroplasmy of Mouse MtDNA is Genetically Unstable and Results in Altered Behavior and Cognition

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Oct 16

PMID 23063123

Citations 175

Authors

Mark S Sharpley

Christine Marciniak

Kristin Eckel-Mahan

Meagan McManus

Marco Crimi

Katrina Waymire

Chun Shi Lin

Satoru Masubuchi

Nicole Friend

Maya Koike

Dimitra Chalkia

Grant MacGregor

Paolo Sassone-Corsi

Douglas C Wallace

Affiliations

Soon will be listed here.

Abstract

Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homoplasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.

Citing Articles

Mitochondrial Transplantation in Animal Models of Psychiatric Disorders: A Novel Approach to Psychiatric Treatment.

Iwata K, Noguchi M, Shintani N Biomolecules. 2025; 15(2).

PMID: 40001487 PMC: 11852835. DOI: 10.3390/biom15020184.

Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood.

Mareckova K, Mendes-Silva A, Jani M, Pacinkova A, Piler P, Goncalves V Transl Psychiatry. 2025; 15(1):16.

PMID: 39837837 PMC: 11751369. DOI: 10.1038/s41398-025-03235-4.

Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling.

Yardeni T, Olali A, Chen H, Wang L, Halton J, Zenab A Proc Natl Acad Sci U S A. 2025; 122(1):e2417252121.

PMID: 39752523 PMC: 11725793. DOI: 10.1073/pnas.2417252121.

Unraveling the role and mechanism of mitochondria in postoperative cognitive dysfunction: a narrative review.

Zhang Z, Yang W, Wang L, Zhu C, Cui S, Wang T J Neuroinflammation. 2024; 21(1):293.

PMID: 39533332 PMC: 11559051. DOI: 10.1186/s12974-024-03285-3.

PET Imaging with [F]ROStrace Detects Oxidative Stress and Predicts Parkinson's Disease Progression in Mice.

Zhu Y, Kohli N, Young A, Sheldon M, Coni J, Rajasekaran M Antioxidants (Basel). 2024; 13(10).

PMID: 39456479 PMC: 11504722. DOI: 10.3390/antiox13101226.

References

Battersby B, Loredo-Osti J, Shoubridge E . Nuclear genetic control of mitochondrial DNA segregation. Nat Genet. 2003; 33(2):183-6. DOI: 10.1038/ng1073. View

Oliver N, Wallace D . Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction. Mol Cell Biol. 1982; 2(1):30-41. PMC: 369750. DOI: 10.1128/mcb.2.1.30-41.1982. View

Sligh J, Levy S, Waymire K, Allard P, Dillehay D, Nusinowitz S . Maternal germ-line transmission of mutant mtDNAs from embryonic stem cell-derived chimeric mice. Proc Natl Acad Sci U S A. 2000; 97(26):14461-6. PMC: 18941. DOI: 10.1073/pnas.250491597. View

Solignac M, Genermont J, Monnerot M, Mounolou J . Drosophila Mitochondrial Genetics: Evolution of Heteroplasmy through Germ Line Cell Divisions. Genetics. 1987; 117(4):687-96. PMC: 1203241. DOI: 10.1093/genetics/117.4.687. View

Sartori S, Whittle N, Hetzenauer A, Singewald N . Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment. Neuropharmacology. 2011; 62(1):304-12. PMC: 3198864. DOI: 10.1016/j.neuropharm.2011.07.027. View

Cree L, Samuels D, Chuva de Sousa Lopes S, Rajasimha H, Wonnapinij P, Mann J . A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet. 2008; 40(2):249-54. DOI: 10.1038/ng.2007.63. View

Jenuth J, Peterson A, Shoubridge E . Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat Genet. 1997; 16(1):93-5. DOI: 10.1038/ng0597-93. View

Porsolt R, Le Pichon M, JALFRE M . Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977; 266(5604):730-2. DOI: 10.1038/266730a0. View

Gindre C, Swendsen J . [Everyday stress, routines and bipolar spectrum]. Encephale. 2010; 36 Suppl 2:D92-6. DOI: 10.1016/j.encep.2008.09.006. View

10.

Etain B, Milhiet V, Bellivier F, Leboyer M . Genetics of circadian rhythms and mood spectrum disorders. Eur Neuropsychopharmacol. 2011; 21 Suppl 4:S676-82. DOI: 10.1016/j.euroneuro.2011.07.007. View

11.

Lane N . Evolution. The costs of breathing. Science. 2011; 334(6053):184-5. DOI: 10.1126/science.1214012. View

12.

Eckel-Mahan K, Sassone-Corsi P . Metabolism control by the circadian clock and vice versa. Nat Struct Mol Biol. 2009; 16(5):462-7. PMC: 4073609. DOI: 10.1038/nsmb.1595. View

13.

Jenuth J, Peterson A, Fu K, Shoubridge E . Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet. 1996; 14(2):146-51. DOI: 10.1038/ng1096-146. View

14.

Wallace D, Ruiz-Pesini E, Mishmar D . mtDNA variation, climatic adaptation, degenerative diseases, and longevity. Cold Spring Harb Symp Quant Biol. 2004; 68:479-86. DOI: 10.1101/sqb.2003.68.471. View

15.

Thompson W, Ramalho-Santos J, Sutovsky P . Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control. Biol Reprod. 2003; 69(1):254-60. DOI: 10.1095/biolreprod.102.010975. View

16.

Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace D . Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004; 303(5655):223-6. DOI: 10.1126/science.1088434. View

17.

Minassian A, Henry B, Young J, Masten V, Geyer M, Perry W . Repeated assessment of exploration and novelty seeking in the human behavioral pattern monitor in bipolar disorder patients and healthy individuals. PLoS One. 2011; 6(8):e24185. PMC: 3166173. DOI: 10.1371/journal.pone.0024185. View

18.

Sutovsky P, McCauley T, Sutovsky M, Day B . Early degradation of paternal mitochondria in domestic pig (Sus scrofa) is prevented by selective proteasomal inhibitors lactacystin and MG132. Biol Reprod. 2003; 68(5):1793-800. DOI: 10.1095/biolreprod.102.012799. View

19.

Alonso S, Castellano M, Afonso D, Rodriguez M . Sex differences in behavioral despair: relationships between behavioral despair and open field activity. Physiol Behav. 1991; 49(1):69-72. DOI: 10.1016/0031-9384(91)90232-d. View

20.

Jokinen R, Marttinen P, Sandell H, Manninen T, Teerenhovi H, Wai T . Gimap3 regulates tissue-specific mitochondrial DNA segregation. PLoS Genet. 2010; 6(10):e1001161. PMC: 2954831. DOI: 10.1371/journal.pgen.1001161. View