TY - JOUR

T1 - Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response

AU - Filograna, R.

AU - Lee, S.

AU - Tiklova, K.

AU - Mennuni, Mara

AU - Jonsson, V.

AU - Ringner, M.

AU - Gilberg, Linda

AU - Сопова, Елена Сергеевна

AU - Шупляков, Олег Викторович

AU - Koolmeister, C.

AU - Olson, L.

AU - Perlmann, T.

AU - Larsson, N.G.

N1 - Publisher Copyright: © 2021 Filograna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/9/27

Y1 - 2021/9/27

N2 - Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson’s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.

AB - Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson’s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.

KW - Animals

KW - DNA, Mitochondrial/genetics

KW - Disease Models, Animal

KW - Dopaminergic Neurons/metabolism

KW - Homeostasis

KW - Immunity

KW - Mesencephalon/metabolism

KW - Mice

KW - Mitochondria/metabolism

KW - Parkinsonian Disorders/genetics

UR - http://www.scopus.com/inward/record.url?scp=85118097032&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/9b00fb24-9eba-3708-a368-14726b30b162/

U2 - 10.1371/journal.pgen.1009822

DO - 10.1371/journal.pgen.1009822

M3 - Article

C2 - 34570766

VL - 17

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 9

M1 - e1009822

ER -