Quality control of mitochondria involves lysosomes in multiple definitive ways

Abstract

Mitochondria are crucial organelles in maintaining cellular homeostasis. They are involved in processes such as energy production, metabolism of lipids and glucose, and cell death regulation. Mitochondrial dysfunction can lead to various health issues such as aging, cancer, neurodegenerative diseases, and chronic liver diseases. While mitophagy is the main process for getting rid of excess or damaged mitochondria, there are additional mechanisms for preserving mitochondrial quality. One such alternative mechanism we have discovered is a hybrid organelle called mitochondrial-lysosome-related-organelle (MLRO), which functions independently of the typical autophagy process. More recently, another type of vesicle called vesicle derived from the inner mitochondrial membrane (VDIM) has been identified to break down the inner mitochondrial membrane without involving the standard autophagy pathway. In this article, we will delve into the similarities and differences between MLRO and VDIM, including their structure, regulation, and relevance to human diseases.

Keywords: Autophagy; DNM1L/DRP1; MLRO; VDIM; mitophagy.

Figure 1.

Multiple pathways of mitochondrial quality control and the comparison between MLRO and VDIM. Representative electron microscopy image of type 1 MLRO (A, arrow) and type 2 MLRO (B, arrow) in primary cultured mouse hepatocytes. (C) various complementary mitochondrial quality control pathways. [1] mitochondrial matrix or intermembrane space proteins can be degraded by AAA ATPase family proteases. [2] mitochondria-associated degradation (MAD): outer mitochondrial membrane (OMM) proteins can be ubiquitinated and degraded by the ubiquitin-proteasome system [3]. Mitochondria-derived vesicles (MDV). [4] mitochondrial spheroids. [5] entire damaged mitochondria can be selectively removed by either autophagosome-involved mitophagy or direct lysosome-mediated micromitophagy. [6] with VDIM the inner mitochondrial membrane is selectively exposed via VDAC1 and degraded by lysosomes [7]. MLRO [8]. Mitocytosis: migrasome-mediated mitochondria secretion. [9] autophagic secretion of mitochondria (ASM). (D) comparison of MLRO and VDIM. OMM: outer mitochondrial membrane, IMM: inner mitochondrial membrane; DNM1L: dynamin 1 like; SNX9: sorting nexin 9; IMMT: inner membrane mitochondrial protein; TSG101: tumor susceptibility 101; TFEB: transcription factor EB; IMS: intermembrane space.