Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Jessica Panes
ORCID logo ,
Thi Kim Oanh Nguyen
,
Huanyao Gao
ORCID logo ,
Trace A Christensen
,
Andrea Stojakovic
,
Sergey Trushin
,
Jeffrey L Salisbury
,
Jorge Fuentealba
* ,
Eugenia Trushina
*
Version 1 : Received: 20 January 2023 / Approved: 27 January 2023 / Online: 27 January 2023 (10:08:59 CET)

A peer-reviewed article of this Preprint also exists.

Panes, J.; Nguyen, T.K.O.; Gao, H.; Christensen, T.A.; Stojakovic, A.; Trushin, S.; Salisbury, J.L.; Fuentealba, J.; Trushina, E. Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice. Cells 2023, 12, 1111. Panes, J.; Nguyen, T.K.O.; Gao, H.; Christensen, T.A.; Stojakovic, A.; Trushin, S.; Salisbury, J.L.; Fuentealba, J.; Trushina, E. Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice. Cells 2023, 12, 1111.

Abstract

Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.

Keywords

Alzheimer’s Disease (AD) mitochondria; endoplasmic reticulum (ER); serial block-face scanning electron microscopy (SBFSEM); three-dimensional electron microscopy (3D EM); small molecule mitochondria targeted therapeutics

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.