Mitochondrial Lon sequesters and stabilizes p53 in the matrix to restrain apoptosis under oxidative stress via its chaperone activity

Abstract

Mitochondrial Lon is a multi-function matrix protease with chaperone activity. However, little literature has been undertaken into detailed investigations on how Lon regulates apoptosis through its chaperone activity. Accumulating evidences indicate that various stresses induce transportation of p53 to mitochondria and activate apoptosis in a transcription-independent manner. Here we found that increased Lon interacts with p53 in mitochondrial matrix and restrains the apoptosis induced by p53 under oxidative stress by rescuing the loss of mitochondrial membrane potential (Δψm) and the release of cytochrome C and SMAC/Diablo. Increased chaperone Lon hampers the transcription-dependent apoptotic function of p53 by reducing the mRNA expression of p53 target genes. The ATPase mutant (K529R) of chaperone Lon decreases the interaction with p53 and fails to inhibit apoptosis. Furthermore, the chaperone activity of Lon is important for mitochondrial p53 accumulation in an mtHsp70-dependent manner, which is also important to prevent the cytosolic distribution of p53 from proteasome-dependent degradation. These results indicate that the chaperone activity of Lon is important to bind with mitochondrial p53 by which increased Lon suppresses the apoptotic function of p53 under oxidative stress. Furthermore, mitochondrial Lon-mtHsp70 increases the stability/level of p53 through trafficking and retaining p53 in mitochondrial matrix and preventing the pool of cytosolic p53 from proteasome-dependent degradation in vitro and in clinic.

P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

“…BMSCs are used to treat early steroid-induced ONFH [43][44][45] ; their survival and stemness in the bone necrotic area are key to the effectiveness of transplantation 46,47 . Studies have revealed an OS microenvironment in the femoral-head necrotic area in which transplanted BMSCs incur a great deal of stress apoptosis and aging, which seriously limits transplantation effectiveness [11][12][13] . More and more studies have shown that mitochondrial dysfunction and damaged-mitochondria accumulation occur before cell stress apoptosis and senescence [19][20][21][22] .…”

“…Central to OS is the release by impaired mitochondria of excessive reactive oxygen species (ROS) and apoptosisinducing factors, which, in turn, increases telomere consumption, arrests the cell cycle, activates signaling pathways such as protein 53 (P53) and protein 38 mitogen-activated protein kinase (P38MAPK), and leads to cellular-stress-induced apoptosis and senescence [13][14][15] . Mitophagy is the most important way to eliminate damaged mitochondria from cells [16][17][18] , it not only promotes mitochondrial renewal but also reduces excessive ROS and apoptosis-inducing factors released by the damaged mitochondria 19 .…”

Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles

“…11 Mitochondrial Lon plays a crucial role in protein quality control, metabolism, mitophagy, and stress response, which maintains the normal function, biogenesis, and homeostasis of mitochondria. 12 13 Lon is a multiple-function protein that has ATPdependent proteolytic, 12 chaperone, [14][15][16] and DNA-binding activity. 17 18 The studies show that Lon plays an important role in mtDNA maintenance and expression, and the strains lacking mitochondrial Lon suffer large deletions in mtDNA in Saccharomyces cerevisiae.…”

PARK7 enhances antioxidative‐stress processes of BMSCs via the ERK1/2 pathway

“…These ROS-induced pathologies can then lead to the release of apoptosis-inducing factors and activation of p53, p38MAPK, and DNA damage response pathways, leading to cellular stress-induced apoptosis and senescence. [25][26][27][28][29][30][31] At present, methods for enhancing antioxidative-stress processes of BMSCs mainly include pretreatments with antioxidants and other drugs. For example, Kim et al 11 pretreated BMSCs with lycopene, which partially improved antioxidativestress processes of BMSCs but ultimately did not have a long-lasting protective effect.…”

“…ROS‐induced damage of mitochondria can lead to dysfunction of the mitochondrial electron‐transport chain, decreased transmembrane potential, and aberrant membrane permeability. These ROS‐induced pathologies can then lead to the release of apoptosis‐inducing factors and activation of p53, p38MAPK, and DNA damage response pathways, leading to cellular stress‐induced apoptosis and senescence 25–31 . At present, methods for enhancing antioxidative‐stress processes of BMSCs mainly include pretreatments with antioxidants and other drugs.…”