A Slc25a46 Mouse Model Simulating Age-Associated Motor Deficit, Redox Imbalance, and Mitochondria Dysfunction

Abstract

The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knock out, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46-/- mice present segmental premature aging phenotypes characterized by shortened lifespan of no more than two months, obviously defective motor ability, gastrocnemius muscle atrophy and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to the mitochondrial dysfunction, which is mainly manifested on the damaged mitochondrial structure (e.g., vacuolar structure, irregular swelling and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46-/- mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

“…Initially described in patients with an optic atrophy spectrum disorder (including axonal sensorimotor neuropathy) [143,144], SLC25A46 variants are also linked to Leigh syndrome [74], progressive myoclonic ataxia with neuropathy [145], cerebellar ataxia [146], pontocerebellar hypoplasia [147,148] and Parkinson Disease [149]. Several animal models, including mouse [150][151][152][153], zebrafish [143], and Drosophila [154], also have neurologic phenotypes that recapitulate human disease. In addition to altered cristae structure and impaired bioenergetics, these animal models show mitochondrial impairment with enlarged mitochondria that have abnormal distribution and which colocalize with the autophagy marker LC3B, consistent with impaired mitophagy.…”

Haematococcus Pluvialis Extends Yeast Lifespan and Improves Slc25a46 Gene Knockout‐Associated Mice Phenotypic Defects

“…MDA as an indirect index and a key marker of oxidative stress usually increased significantly in the brain, consistent with the finding in the brain of Slc25a46-/-mice. [18] In such cases, MDA, as a mitochondrial toxin, in turn suppresses oxidative phosphorylation in the mitochondria resulting in energy dysmetabolism, and this which forms a vicious cycle. The identified oxidative stress in the brain could account for the impaired mitochondrial function.…”

“…Mitochondrial respiratory chain deficits were found in the Slc25a46-/-mice, especially complex I and IV. [18] Complex I (protein level of ADH dehydrogenase) is closely associated with proton pumping activity, which affect ATP generation. [50] Complex IV is most relevant to aging in relation to the mitochondrial electron transport systems of both insect and mammalian species.…”

“…Previously, we have shown that the mitochondrial outer membrane protein (Slc25a46) knockout mouse model with shortenedlifespan and other mitochondrial-related deficit symptoms is a valid animal model for segmental aging-related pathological studies based on the mitochondrial theory as well as for the screening of potential bioactive substances. [18] Therefore, to further explore the effect of H. pluvialis extracts in improving agingrelated pathologies in vivo, Slc25a46-/-mouse model was used to evaluate this functions (Figure 3A). Slc25a46-/-mice showed no difference in body weight before any interventions (p > 0.05, SLC-Veh vs SLC-H. pluvialis), while there was a significant difference between the Slc25a46-/-and WT mice (p < 0.05, Figure 3B), suggesting that Slc25a46-/-grew with a weight defect.…”

Bringing to fore the role of peptides, polyphenols, and polysaccharides in health: The research profile of Jiaoyan Ren

“…Furthermore, she has established an in vivo slc25a46 knockout mouse model to explore the role and effect of the mitochondria and mitochondria injury in various health conditions and how bioactive food components could modulate these effects (Gao et al., 2020).…”