# The Role of Altered Mitochondrial Contact Site and Cristae Organizing System (MICOS) in Alzheimer's Disease

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $80,417

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondrial deficits is one of the early and prominent features of Alzheimer’s disease and a large body of
studies suggest mitochondrial dysfunction could trigger the pathogenesis of AD. However, the underlying
mechanism remains elusive. Recent progress in mitochondrial studies highlight the unique mitochondrial
structural system and its implication under both physiological and pathological conditions. In particular, it is
well known that mitochondrial inner membrane connects outer membrane by the individual contact site,
which forms neck-like tubule to communicate inter-membrane space and intra-cristae space. A growing body
of studies unveiled the molecular machinery in maintaining the integrity of mitochondria by the mitochondrial
contact site and cristae organizing system (MICOS). It is not surprising that impaired MICOS greatly
deteriorates mitochondrial morphology and function. Importantly, abnormal MICOS is associated with
several human diseases including nervous diseases, which underscores the significance of analyzing the
MICOS in the most prevalent neurodegenerative disease in the world. In this regard, we investigated the
integrity of MICOS in human brains of AD and control cases. Our preliminary data suggest there were
changes of MICOS related mitochondrial cristae structure in the cortical neurons of human AD brains by
electron microscopy analysis. In addition, there were deficits in proteins levels, neuronal distributions of core
MICSOS components and assembly of MICOS complex in human AD brains in the pilot study. Altogether,
both structural and biochemical analysis suggested the impaired MICOS in AD brain. These exciting
discoveries raised a critical question of whether and how impaired neuronal MICOS contributed to the
mitochondrial dysfunction and neuronal loss in the AD. In this application, as the first step to
characterize the potential role of abnormal MICOS changes in mitochondrial dysfunction and pathogenesis
of AD, we will explore the changes of MICOS and its consequences and correlation with other
mitochondrial/neuronal deficits in AD models both in vitro and in vivo. As the first study to specifically
determine the potential involvement of MICOS abnormalities in causing mitochondrial dysfunction and
pathogenesis of AD, our proposal will likely pave the road for larger studies to shed new light on a novel
mechanism underlying mitochondrial dysfunction in the pathogenesis of AD and provide innovative
therapeutic targets for future drug development to fight against AD.

## Key facts

- **NIH application ID:** 9986607
- **Project number:** 5R03AG063362-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Wenzhang Wang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $80,417
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986607

## Citation

> US National Institutes of Health, RePORTER application 9986607, The Role of Altered Mitochondrial Contact Site and Cristae Organizing System (MICOS) in Alzheimer's Disease (5R03AG063362-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9986607. Licensed CC0.

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