Discovery of Mieap-regulated mitochondrial quality control as a new function of tumor suppressor p53 - PubMed (original) (raw)

Review

. 2017 May;108(5):809-817.

doi: 10.1111/cas.13208. Epub 2017 May 5.

Affiliations

Review

Discovery of Mieap-regulated mitochondrial quality control as a new function of tumor suppressor p53

Yasuyuki Nakamura et al. Cancer Sci. 2017 May.

Abstract

The tumor suppressor p53 gene is frequently mutated in human cancers, and the p53 protein suppresses cancer. However, the mechanism behind the p53-mediated tumor suppression is still unclear. Recently, the mitochondria-eating protein (Mieap) was identified as a p53-inducible protein. Mieap induces the accumulation of lysosomal proteins within mitochondria (Mieap-induced accumulation of lysosome-like organelles within mitochondria, or MALM) in response to mitochondrial damage, and eliminates the oxidized mitochondrial proteins to repair unhealthy mitochondria. Furthermore, Mieap also induces vacuole-like structures (Mieap-induced vacuole, or MIV) to eat and degrade unhealthy mitochondria. Therefore, Mieap controls mitochondrial quality by repairing or eliminating unhealthy mitochondria by MALM or MIV, respectively. This mechanism is not mediated by canonical autophagy. Mieap-deficient ApcMin/+ mice show strikingly high rates of intestinal tumor development as well as advanced-grade adenomas and adenocarcinomas. The p53/Mieap/BCL2 interacting protein 3 mitochondrial quality control pathway is frequently inactivated in human colorectal cancers. Defects in Mieap-regulated mitochondrial quality control lead to accumulation of unhealthy mitochondria in cancer cells. Cancer-specific unhealthy mitochondria could contribute to cancer development and aggressiveness through mitochondrial reactive oxygen species and altered metabolism. Mieap-regulated mitochondrial quality control is a newly discovered function of p53 that plays a critical role in tumor suppression.

Keywords: Autophagy; cancer metabolism; mitochondrial quality control; reactive oxygen species; tumor suppressor p53.

© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Tumor suppressor p53 regulates a large number of functions through transcriptional activation of its target genes as a transcription factor. Apoptosis, cell cycle arrest,

DNA

repair, and anti‐angiogenesis are believed to be the core functions for p53‐mediated tumor suppression. Mieap is a p53‐target gene, and the function is involved in mitochondrial quality control.

Figure 2

Figure 2

Mitochondria‐eating protein (Mieap)‐regulated mitochondrial quality control. In response to mitochondrial damage, p53‐activated Mieap induces accumulation of lysosomal proteins within mitochondria to eliminate the oxidized mitochondrial proteins (

MALM

). The

MALM

repairs unhealthy mitochondria. Mieap also induces large vacuole‐like structures (

MIV

) to eat and degrade very dangerous and unhealthy mitochondria producing high levels of reactive oxygen species (

ROS

). Therefore, p53/Mieap maintains mitochondrial integrity by repairing or eliminating unhealthy mitochondria by

MALM

or

MIV

, respectively. Lyso, lysosome.

Figure 3

Figure 3

Hypothetical model for the mitochondria‐eating protein (Mieap)‐induced accumulation of lysosome‐like organelles within mitochondria (

MALM

) mechanism. Unhealthy mitochondria produce high level of reactive oxygen species (

ROS

). Mitochondrial

ROS

induces the interaction of Mieap and two mitochondrial outer‐membrane proteins,

BCL

2 interacting protein 3 (

BNIP

  1. and

NIX

. The interaction of Mieap,

BNIP

3, and

NIX

leads to the formation of a pore, through which lysosomal proteins or lysosome‐like organelles accumulate within mitochondria. 14‐3‐3γ interacts with Mieap in cytosol, and translocates into the mitochondria, which mediates the elimination of the oxidized mitochondrial proteins in the mitochondria. Therefore,

MALM

maintains the healthy status of the mitochondria, indicating an increase of

ATP

synthesis activity and a decrease of

ROS

generation.

CMA

, chaperone‐mediated autophagy.

Figure 4

Figure 4

Hypothetical model for the mitochondria‐eating protein (Mieap)‐induced vacuole (

MIV

) mechanism. Severely damaged and dangerous mitochondria produce very high levels of reactive oxygen species (

ROS

), which are extremely toxic to the cell. These

ROS

induce the generation of

MIV

s. The

MIV

s uptake and degrade the dangerous mitochondria to maintain cellular homeostasis.

UV

radiation resistance associated gene (

UVRAG

) protein mediates the

MIV

formation by interacting with Mieap. The endocytic pathway also plays a critical role in

MIV

formation. Lyso, lysosome.

Figure 5

Figure 5

Interplay between mitochondria‐eating protein (Mieap)‐induced accumulation of lysosome‐like organelles within mitochondria (

MALM

) and Mieap‐induced vacuoles (

MIV

): repair? Or elimination? Four cancer cell lines derived from A549 (lung cancer cell line), control,

NIX

‐knockdown (

KD

), p53‐

KD

, and Mieap‐

KD

, were irradiated by ionizing radiation (

IR

). 3 days after

IR

, immunostaining experiments were carried out with anti‐Mieap antibody (Mieap), anti‐cathepsin D antibody (Cathepsin‐D), and DsRed‐mito (Mitochondria).

MALM

occurred in the control cells, in which the colocalization of Mieap, lysosome, and mitochondria is observed (yellow signals). When

MALM

is inhibited by

NIX

‐

KD

,

MIV

s appear, eat, and degrade the mitochondria in the

NIX

‐

KD

cells. Both

MALM

and

MIV

are cancelled in the p53‐

KD

and Mieap‐

KD

cells. Therefore,

MALM

and

MIV

are closely related to each other when making a decision about repair or elimination of unhealthy mitochondria. Both

MALM

and

MIV

are strictly regulated by the p53/Mieap pathway. Reproduced from Kitamura et al.37 with permission from.

EM

, electron microscopy.

Figure 6

Figure 6

Cancer‐specific unhealthy mitochondria in the hypoxic tumor microenvironment function as a driving force for cancer development and progression. In human cancer, mitochondria‐eating protein (Mieap)‐regulated mitochondrial quality control is frequently inactivated by p53 mutations and/or Mieap/

BCL

2 interacting protein 3 (

BNIP

  1. promoter methylation. This leads to the accumulation of cancer specific unhealthy mitochondria in the hypoxic tumor microenvironment. Cancer‐specific unhealthy mitochondria produce high levels of

ROS

. Mitochondrial

ROS

induce oxidative damage and genomic instability, and promote tumor growth, cancer invasion, metastasis, and tumor angiogenesis. Cancer specific unhealthy mitochondria also causes altered metabolism including activation of fatty acid synthesis, nucleic acid synthesis, glutamate metabolism, and one carbon metabolism, defective oxidative phosphorylation, and upregulation of glycolysis. Therefore, mitochondrial reactive oxygen species (

ROS

) and altered metabolism caused by cancer‐specific unhealthy mitochondria could greatly contribute to cancer development and progression.

Similar articles

Cited by

References

    1. Lane DP, Crawford LV. T antigen is bound to a host protein in SV40‐transformed cells. Nature 1979; 278: 261–3. - PubMed
    1. Linzer DI, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40‐transformed cells and uninfected embryonal carcinoma cells. Cell 1979; 17: 43–52. - PubMed
    1. Kress M, May E, Cassingena R, May P. Simian virus 40‐transformed cells express new species of proteins precipitated by anti‐simian virus 40 tumor serum. J Virol 1979; 31: 472–83. - PMC - PubMed
    1. Melero JA, Stitt DT, Mangel WF, Carroll RB. Identification of new polypeptide species [48‐55K] immunoprecipitated by antiserum to purified large T antigen and present in SV40‐infected and transformed cells. Virology 1979; 93: 466–80. - PubMed
    1. Smith AE, Smith R, Paucha E. Characterization of different tumor antigens present in cells transformed by simian virus 40. Cell 1979; 18: 335–46. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources