Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control.
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.
Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Tokyo, Japan.
Yuji
Y
Miyamoto
Noriaki
N
Kitamura
Yasuyuki
Y
Nakamura
Manabu
M
Futamura
Takafumi
T
Miyamoto
Masaki
M
Yoshida
Masaya
M
Ono
Shizuko
S
Ichinose
Hirofumi
H
Arakawa
D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015388:Organelles / Q000737:chemistry*; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D024101:Mitochondrial Proteins; C558496:SPATA18 protein, human; D016159:Tumor Suppressor Protein p53
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