Format

Send to

Choose Destination
Exp Gerontol. 2019 Oct 1;125:110675. doi: 10.1016/j.exger.2019.110675. Epub 2019 Jul 22.

Increased burden of mitochondrial DNA deletions and point mutations in early-onset age-related hearing loss in mitochondrial mutator mice.

Author information

1
Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
2
Center for Mitochondrial and Epigenomic Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Center for Hearing and Deafness, State University of New York at Buffalo, NY, USA.
4
Department of Medicine, University of California, Los Angeles, CA, USA.
5
Gene Expression & Genotyping, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL, USA.
6
Whitney Laboratory, University of Florida, St Augustine, FL, USA.
7
Department of Applied Biological Chemistry, University of Tokyo, Yayoi, Tokyo, Japan.
8
Department of Genetics, University of Wisconsin, Madison, WI, USA.
9
Center for Hearing and Deafness, State University of New York at Buffalo, NY, USA; Department of Audiology and Speech-Language Pathology, Asia University, Taichung, Taiwan, ROC.
10
Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA. Electronic address: someya@ufl.edu.

Abstract

Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in a variety of age-related neurodegenerative diseases, including age-related hearing loss (AHL). In the current study, we investigated the roles of mtDNA deletions and point mutations in AHL in mitochondrial mutator mice (Polgmut/mut) that were backcrossed onto CBA/CaJ mice, a well-established model of late-onset AHL. mtDNA deletions accumulated significantly with age in the inner ears of Polgmut/mut mice, while there were no differences in mtDNA deletion frequencies in the inner ears between 5 and 17 months old Polg+/+ mice or 5 months old Polg+/+ and Polgmut/mut mice. mtDNA deletions also accumulated significantly in the inner ears of CBA/CaJ mice during normal aging. In contrast, 5 months old Polgmut/mut mice displayed a 238-fold increase in mtDNA point mutation frequencies in the inner ears compared to age-matched Polg+/+ mice, but there were no differences in mtDNA point mutation frequencies in the inner ears between 5 and 17 months old Polgmut/mut mice. Seventeen-month-old Polgmut/mut mice also displayed early-onset severe hearing loss associated with a significant reduction in neural output of the cochlea, while age-matched Polg+/+ mice displayed little or no hearing impairment. Consistent with the physiological and mtDNA deletion test result, 17-month-old Polgmut/mut mice displayed a profound loss of spiral ganglion neurons in the cochlea. Thus, our data suggest that a higher burden of mtDNA point mutations from a young age and age-related accumulation of mtDNA deletions likely contribute to early-onset AHL in mitochondrial mutator mice.

KEYWORDS:

Aging; Hearing loss; Mitochondrial DNA mutations; Mitochondrial disease

PMID:
31344454
PMCID:
PMC6857812
[Available on 2020-10-01]
DOI:
10.1016/j.exger.2019.110675

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center