# Long-lived proteins as pillars of mitochondrial architecture in rodent brains

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2023 · $200,000

## Abstract

ABSTRACT
Mitochondria are multifaceted organelles that play vital roles in a myriad of cellular functions, including energy
production, metabolism, calcium homeostasis, and cell death. It is generally accepted that a decline in
mitochondria quality is a key contributor to mitochondrial dysfunction, aging, and represents a key point of
convergence for several neurological disorders. Yet, precisely how dysfunctional mitochondria contribute to
these conditions remains elusive. Proper mitochondrial function and fitness depends on a healthy proteome.
Therefore, the mitochondrial proteome is monitored by an elaborate and integrated protein quality control
network. Recent studies in mice have found that, on average, half-lives of mitochondrial proteins in the brain
vary from minutes to days. Notably, our own recent discovery-based proteomic analysis revealed that a small
subset of mitochondrial proteome persists for months in brain, heart, and eyeball in mice and rats. Given the vital
role of mitochondria in cell health and survival, and the highly dynamic nature of mitochondria our discovery that
mitochondrial proteins can persist for months in healthy tissues is unexpected and of potential importance.
The overarching goal of this project is to characterize mitochondrial long-lived proteins (mt-LLPs) in the context
of mitochondrial homeostasis. Our current understanding of mt-LLPs are based on composite measures from
tissue homogenates and we lack an understanding of which specific cell types harbor these exceptional proteins.
Several lines of evidence point to an inevitable dichotomy of proteins with exceptionally long lifespans. On one
hand, due to their persistence, mt-LLPs serve as pillars of mitochondrial architecture, providing structural stability
ensure a compact energy generating chemical reactor. At the same time, their long-term persistence puts LLPs
at an inherently increased risk for age-related deterioration. Thus, our overall objectives are to use whole-
animal stable isotope pulse labelling combined with biochemical and proteomic analyses to identify the brain cell
types harboring mt-LLPs (Aim 1) and in parallel investigate mtDNA lifetime (Aim 2). Finally, we aim to determine
if cristae structural integrity is required for mt-LLP persistence (Aim 3.1) and correlate the presence of mt-LLPs
with mitochondrial membrane potential (Aim 3.2). Understanding the cells and structures harboring mt-LLPs,
and the effect on mitochondrial fitness, could open new avenues of research and provide molecular targets for
modulating mitochondrial network dynamics in the process of age-related neurodegeneration.

## Key facts

- **NIH application ID:** 10698113
- **Project number:** 5R21AG072343-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jeffrey Nicholas Savas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10698113

## Citation

> US National Institutes of Health, RePORTER application 10698113, Long-lived proteins as pillars of mitochondrial architecture in rodent brains (5R21AG072343-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10698113. Licensed CC0.

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