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Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control.

Miyamoto Y, Kitamura N, Nakamura Y, Futamura M, Miyamoto T, Yoshida M, Ono M, Ichinose S, Arakawa H - PLoS ONE (2011)

Bottom Line: MALM was not related to canonical autophagy.MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation.These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins.

View Article: PubMed Central - PubMed

Affiliation: Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT
The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect.

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Related in: MedlinePlus

Post-embedding immunoelectron microscopic analysis shows the presence of Mieap and lysosomal proteins within mitochondria.The Ad-Mieap and Ad-LacZ infected cells of HCT116 were subjected to post-embedding imunoelectron microscopic analysis with gold particles on day 3 after IR. The primary antibody against Mieap (A), cathepsin D (B), or LAMP1 (C) was used for the analysis. The representative images are shown. m: mitochondria Scale bar = 200 nm.
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pone-0016054-g006: Post-embedding immunoelectron microscopic analysis shows the presence of Mieap and lysosomal proteins within mitochondria.The Ad-Mieap and Ad-LacZ infected cells of HCT116 were subjected to post-embedding imunoelectron microscopic analysis with gold particles on day 3 after IR. The primary antibody against Mieap (A), cathepsin D (B), or LAMP1 (C) was used for the analysis. The representative images are shown. m: mitochondria Scale bar = 200 nm.

Mentions: To confirm the results of the pre-embedding method, we carried out post-embedding immunoelectron microscopic analysis using gold particles and primary antibodies against Mieap, LAMP1, or cathepsin D. Consistent with the result of the pre-embedding method, gold particle clusters indicating Mieap, cathepsin D, or LAMP1 labeling were observed within the mitochondria of Ad-Mieap-infected HCT116 cells on day 3 after IR, whereas no clusters were detected in the mitochondria of Ad-LacZ-infected cells (Figure 6A–6C). Furthermore, at high magnification, all Mieap, cathepsin D, and LAMP1 proteins may have been predominantly localized to the mitochondrial matrix (Figures S15, S16).


Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control.

Miyamoto Y, Kitamura N, Nakamura Y, Futamura M, Miyamoto T, Yoshida M, Ono M, Ichinose S, Arakawa H - PLoS ONE (2011)

Post-embedding immunoelectron microscopic analysis shows the presence of Mieap and lysosomal proteins within mitochondria.The Ad-Mieap and Ad-LacZ infected cells of HCT116 were subjected to post-embedding imunoelectron microscopic analysis with gold particles on day 3 after IR. The primary antibody against Mieap (A), cathepsin D (B), or LAMP1 (C) was used for the analysis. The representative images are shown. m: mitochondria Scale bar = 200 nm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3022026&req=5

pone-0016054-g006: Post-embedding immunoelectron microscopic analysis shows the presence of Mieap and lysosomal proteins within mitochondria.The Ad-Mieap and Ad-LacZ infected cells of HCT116 were subjected to post-embedding imunoelectron microscopic analysis with gold particles on day 3 after IR. The primary antibody against Mieap (A), cathepsin D (B), or LAMP1 (C) was used for the analysis. The representative images are shown. m: mitochondria Scale bar = 200 nm.
Mentions: To confirm the results of the pre-embedding method, we carried out post-embedding immunoelectron microscopic analysis using gold particles and primary antibodies against Mieap, LAMP1, or cathepsin D. Consistent with the result of the pre-embedding method, gold particle clusters indicating Mieap, cathepsin D, or LAMP1 labeling were observed within the mitochondria of Ad-Mieap-infected HCT116 cells on day 3 after IR, whereas no clusters were detected in the mitochondria of Ad-LacZ-infected cells (Figure 6A–6C). Furthermore, at high magnification, all Mieap, cathepsin D, and LAMP1 proteins may have been predominantly localized to the mitochondrial matrix (Figures S15, S16).

Bottom Line: MALM was not related to canonical autophagy.MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation.These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins.

View Article: PubMed Central - PubMed

Affiliation: Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT
The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect.

Show MeSH
Related in: MedlinePlus