Possible Existence of Lysosome-Like Organella within Mitochondria and Its Role in Mitochondrial Quality Control

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.

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

“…It is known that a TP53-inducible protein, Mieap (also referred to as Spata18) (18), controls mitochondrial quality through interaction with the HIF-1-inducible protein BNIP3 (19). In addition, Mieap has been proposed to induce the accumulation of lysosomal proteins within mitochondria by way of repairing damaged mitochondria (20).…”

Distinct p53 genomic binding patterns in normal and cancer-derived human cells

“…70 The expression of the same gene (under the name Mieap), was characterized in several human cell lines and was shown to play a role in mitochondria quality control. 71 Notably, SPATA18 is silenced by DNA methylation in several cancer cell lines, including HCT116. We believe that the functional clusters provided here represent a good source for examining potential p53-related functions in normal cells.…”

Protéger et sévir : p53, métabolisme et suppression tumorale

“…Si ce tableau souligne la régulation du métabolisme énergétique par p53, la réciproque (non montrée ici) est tout aussi vraie [7,17,24,28]. [20,42] Basale (surtout) et induite [54] Version conditionnelle de p53 [24] Basale et induite [24,40] Basale et induite [32,41] Basale et induite [31] Voie des pentoses phosphates G6PD (glucose 6 phosphate déshydro-génase) Enzyme limitante de la voie des pentoses phosphates Interaction protéine/protéine inhibitrice Basale et induite [21] Figure 4. Fonctions conservatrices et destructrices de p53 dans la suppression tumorale.…”

“…La suppression tumorale dépend alors surtout des activités destructrices associées à une expression élevée de p53 et en partie liées à ses effets pro-oxydants : sénescence (cellule plus grande) et apoptose (croix sur la cellule). L'induction de l'autophagie (croix dans la cellule) représente un cas intermédiaire entre A et B : elle apparaît comme une fonction conservatrice, puisque l'élimination d'organites défectueux (notamment les mitochondries) et le recyclage de leurs constituants peuvent maintenir le métabolisme oxydatif et assurer la survie des cellules dans certaines situations [31,32]. Dans d'autres circonstances cependant, elle contribue à la sénescence ou à l'apoptose et participe donc aux fonctions destructrices responsables de la suppression tumorale « induite » [53].…”