Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria.
Maintenance of healthy mitochondria prevents aging, cancer, and a variety of degenerative diseases that are due to the result of defective mitochondrial quality control (MQC). Recently, we discovered a novel mechanism for MQC, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria). However, a large part of the mechanisms for MQC remains unknown. Here, we report additional mechanisms for Mieap-regulated MQC. Reactive oxygen species (ROS) scavengers completely inhibited MALM. A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. Deficiency of NIX also completely impaired MALM. When MALM was inhibited, Mieap induced vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulfed and degraded the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impaired both MALM and MIV generation, leading to accumulation of unhealthy mitochondria. These results suggest that (1) mitochondrial ROS and NIX are essential factors for MALM, (2) MIV is a novel mechanism for lysosomal degradation of mitochondria, and (3) the p53-Mieap pathway plays a pivotal role in MQC by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively.
Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Tokyo, Japan.
Noriaki
N
Kitamura
Yasuyuki
Y
Nakamura
Yuji
Y
Miyamoto
Takafumi
T
Miyamoto
Koki
K
Kabu
Masaki
M
Yoshida
Manabu
M
Futamura
Shizuko
S
Ichinose
Hirofumi
H
Arakawa
D002460:Cell Line; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology*; D015388:Organelles / Q000737:chemistry*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
C116838:BNIP3L protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C558496:SPATA18 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
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