Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1

Author:

Wang Wenzhang1ORCID,Ma Xiaopin1,Bhatta Sabina1,Shao Changjuan1,Zhao Fanpeng1,Fujioka Hisashi2ORCID,Torres Sandy1ORCID,Wu Fengqin1,Zhu Xiongwei1ORCID

Affiliation:

1. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106

2. Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, OH 44106

Abstract

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m 6 A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

Funder

HHS | National Institutes of Health

Alzheimer's Association

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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