Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Sep-Oct;1819(9-10):1080-7.
doi: 10.1016/j.bbagrm.2011.11.008. Epub 2011 Dec 8.

Matrix proteases in mitochondrial DNA function

Yuichi Matsushima  1 , Laurie S Kaguni
Affiliations
Review

Matrix proteases in mitochondrial DNA function

Yuichi Matsushima et al. Biochim Biophys Acta. 2012 Sep-Oct.

Abstract

Lon, ClpXP and m-AAA are the three major ATP-dependent proteases in the mitochondrial matrix. All three are involved in general quality control by degrading damaged or abnormal proteins. In addition to this role, they are proposed to serve roles in mitochondrial DNA functions including packaging and stability, replication, transcription and translation. In particular, Lon has been implicated in mtDNA metabolism in yeast, fly and humans. Here, we review the role of Lon protease in mitochondrial DNA functions, and discuss a putative physiological role for mitochondrial transcription factor A (TFAM) degradation by Lon protease. We also discuss the possible roles of m-AAA and ClpXP in mitochondrial DNA functions, and the putative candidate substrates for the three matrix proteases. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.

PubMed Disclaimer

Figures

Figure 1
Figure 1. AAA+ proteases in the mitochondrial matrix
Lon, ClpXP and m-AAA are the three major proteases in the animal mitochondrial matrix. Lon and ClpXP localize in the mitochondrial matrix per se, whereas the m-AAA protease is membrane anchored to expose its catalytic site to the matrix space. Lon forms a ring-shaped homo-oligomeric structure, and m-AAA forms homo- or hetero-oligomeric structures. ClpXP is composed of two subunits, ClpP and ClpX; it is a hetero-oligomeric complex in which ClpP forms a two-stack heptameric ring-shaped structure to which two hexameric ClpX rings bind on each side. Some mitochondrial proteins, such as TFAM, mtDNA replication factors, etc., bind to mtDNA to package it into a structure called the mitochondrial nucleoid. Lon is also a component of the mitochondrial nucleoid.
Figure 2
Figure 2. Domain strucure of the Lon protease
Lon comprises three domains, an N-terminal domain, central AAA+ ATPase domain, and a C-terminal protease domain. The N-terminal domain is involved in oligomerization and protein substrate binding. The AAA+ domain that contributes ATP binding and hydrolysis consists of two sub-domains, an α/β domain and an α domain. The DNA-binding domains in E. coli and B. thermoruber Lon reside in different regions within the AAA+ module, and that in mitochondrial Lon has not been localized. The C-terminal protease domain contains a serine and lysine dyad in the active site.
Figure 3
Figure 3. mtDNA and TFAM function in an interdependent manner
Upper panel, Upon mtDNA depletion, TFAM is degraded by the Lon protease; middle panel, mtDNA and TFAM stabilize each other; lower panel, reduction of TFAM results in depletion of mtDNA.
Figure 4
Figure 4. Lon protease degrades TFAM to stabilize the TFAM: mtDNA ratio
A, Upon reduction of mtDNA copy number in normal cells, Lon degrades TFAM to normalize the TFAM: mtDNA ratio. As a result of this process, mtDNA transcription occurs normally. B, Upon mtDNA reduction in Lon-depleted cells, TFAM is not degraded, resulting in a dramatic increase in the TFAM: mtDNA ratio. This results in a severe inhibition in mtDNA transcription, which is likely caused by mtDNA overpackaging by TFAM. C, Excess TFAM overexpression leads to an increase in the TFAM: mtDNA ratio, resulting in a severe inhibition in mtDNA transcription.
Figure 5
Figure 5. Potential physiological roles of the AAA+ proteases in mtDNA function
The model shows that the three AAA+ proteases in the mitochondrial matrix regulate mitochondrial protein levels to sustain proper mtDNA functions, such as mtDNA packaging and stability, replication, transcription and translation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ugarte N, Petropoulos I, Friguet B. Oxidized mitochondrial protein degradation and repair in aging and oxidative stress. Antioxid Redox Signal. 2010;13:539–549. - PubMed
    1. Truscott KN, Lowth BR, Strack PR, Dougan DA. Diverse functions of mitochondrial AAA+ proteins: protein activation, disaggregation, and degradation. Biochem Cell Biol. 2010;88:97–108. - PubMed
    1. Baker MJ, Tatsuta T, Langer T. Quality control of mitochondrial proteostasis. Cold Spring Harb Perspect Biol. 2011;3 - PMC - PubMed
    1. Garcia-Nafria J, Ondrovicova G, Blagova E, Levdikov VM, Bauer JA, Suzuki CK, Kutejova E, Wilkinson AJ, Wilson KS. Structure of the catalytic domain of the human mitochondrial Lon protease: proposed relation of oligomer formation and activity. Protein Sci. 2010;19:987–999. - PMC - PubMed
    1. Stahlberg H, Kutejova E, Suda K, Wolpensinger B, Lustig A, Schatz G, Engel A, Suzuki CK. Mitochondrial Lon of Saccharomyces cerevisiae is a ring-shaped protease with seven flexible subunits. Proc Natl Acad Sci U S A. 1999;96:6787–6790. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources