Interorganelle Communication between Mitochondria and the Endolysosomal System

Abstract

The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis.

Keywords: aging; autophagy; exosomes; lysosome; proteostasis; quality control.

Figure 1

Crosstalk between the mitochondria and lysosomal vacuole in yeast. Two different mechanisms exist for molecular exchange between the mitochondria and lysosomal vacuole: vesicular transport and physical contacts. Mitochondrial membrane proteins can be transported from the mitochondria to the vacuole through the formation of the mitochondrial derived compartment (MDC), particularly for their degradation by autophagy. This mechanism is a protective pathway to preserve mitochondrial integrity in times of stress. In addition, mitochondria and the lysosomal vacuole establish physical contacts, the vacuole and mitochondria patch (vCLAMP), which involves the Vps39, Ypt7, and Lam6 proteins and an unidentified mitochondrial component. This connection participates in the exchange of nutrients and lipids between these organelles. Lam6 is also present in endoplasmic reticulum-mitochondria encounter structure (ERMES), the physical contact between mitochondria and the endoplasmic reticulum. The presence of Lam6 in both mitochondrial contacts makes their co-regulation possible. Hence, vCLAMP is more extensively distributed in an ERMES mutant and conversely, there are more ERMES when vCLAMP is impaired. MDC, Mitochondrial derived compartment; vCLAMP, vacuole and mitochondria patch; ERMES, endoplasmic reticulum-mitochondria encounter structure; (?), unidentified mitochondrial component of vCLAMP.

Figure 2

Different means of communication between the mitochondria and lysosome in mammals. Emerging evidence supports the existence of intense crosstalk between the mitochondria and the endolysosomal compartment in mammals. Functional stress or dysfunction of one organelle affects the other. Thus, mitochondrial stress induces a secondary lysosomal dysfunction, which produces activation of TFEB and a transcriptional response associated with lysosomal biogenesis. Additionally, under conditions of stress, mitochondrial derived vesicles (MDVs) are formed in a process dependent on parkin and PINK1. These MDVs traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation, a fast response established to remove oxidized proteins. Once in the endolysosomal route, the mitochondrial content can be degraded by lysosomal enzymes or released to the extracellular milieu via exosomes. Physical connections between the mitochondria and lysosome or melanosome are required for local ATP supply, Ca²⁺ homeostasis, Fe²⁺ transport and to process VDAC1. Mfn2 regulates the mitochondria-melanosome physical connection. MVB, Multivesicular body; MDVs, Mitochondrial-derived vesicles; PINK1, PTEN-induced kinase 1; VDAC1, mitochondrial voltage-dependent anion channel isoform 1; Mfn2, Mitofusin2; TFEB, Transcription Factor EB.