Abstract
Long-lived proteins (LLPs) have recently emerged as vital components of intracellular structures whose function is coupled to long-term stability. Mitochondria are multifaceted organelles, and their function hinges on efficient proteome renewal and replacement. Here, using metabolic stable isotope labeling of mice combined with mass spectrometry (MS)–based proteomic analysis, we demonstrate remarkable longevity for a subset of the mitochondrial proteome. We discovered that mitochondrial LLPs (mt-LLPs) can persist for months in tissues harboring long-lived cells, such as brain and heart. Our analysis revealed enrichment of mt-LLPs within the inner mitochondrial membrane, specifically in the cristae subcompartment, and demonstrates that the mitochondrial proteome is not turned over in bulk. Pioneering cross-linking experiments revealed that mt-LLPs are spatially restricted and copreserved within protein OXPHOS complexes, with limited subunit exchange throughout their lifetimes. This study provides an explanation for the exceptional mitochondrial protein lifetimes and supports the concept that LLPs provide key structural stability to multiple large and dynamic intracellular structures.
Original language | English (US) |
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Article number | e202005193 |
Journal | Journal of Cell Biology |
Volume | 220 |
Issue number | 9 |
DOIs | |
State | Published - 2021 |
Funding
E. Bomba-Warczak was supported by the National Institutes of Health (F32 NS106812, National Institute of Neurological Disorders and Stroke); this research was also supported by R21HD098498 (National Institute of Child Health and Human Development), R21NS107761 (National Institute of Neurological Disorders and Stroke), and R01AG061787 (National Institute of Aging) to J.N. Savas. This work used resources of the Northwestern University Structural Biology Facility, which is generously supported by a National Cancer Institute CCSG P30 CA060553 grant awarded to the Robert H. Lurie Comprehensive Cancer Center. The authors declare no competing financial interests.
ASJC Scopus subject areas
- Cell Biology