Function of lysosomes and mitochondria

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Mansueto, G. Transcription factor EB controls metabolic flexibility during exercise.

Function of lysosomes and mitochondria

TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Wada, S. Non-canonical mTORC1 signaling at the lysosome. Trends Cell Biol. Jansen, R. Cui, Z. Marchand, B. Glycogen synthase kinase-3 GSK3 inhibition induces prosurvival autophagic signals in human pancreatic cancer cells. Ploper, D. MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells.

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This mechanism would prevent the cytosolic accumulation of iron, which can catalyze the formation of damaging ROS. A second essential role of lysosomes is the degradation of macromolecules, generating free amino acids, sugars and lipids that can be used in biosynthetic pathways or for energy production. As mitochondria are a major metabolic hub, lysosome, and mitochondria could regulate the function of each other through the production, transfer, or degradation of metabolites.

In support of this hypothesis, mitochondria-lysosome contact sites participate in the transfer of phospholipids between the two organelles Elbaz-Alon et al. Furthermore, respiratory growth on non-fermentable carbon sources in yeast increased ER-mitochondria contact sites at the expense of mitochondria-lysosome contacts sites Honscher et al. Their activation close to mitochondria could increase mitochondrial uptake of these ions, both of which stimulate mitochondrial activity Figure 1 , Box 2; Hackenbrock, ; Yamanaka et al.

The close proximity of mitochondria and lysosomes could thus similarly provide an easy access to amino acids generated by lysosomal proteolysis, especially during starvation Figure 1 , Box 2. However, the role of lysosomes in amino acid homeostasis extends well beyond protein degradation. In fact, lysosomes serve as a platform to sense amino acid contents both outside and inside of the organelle Bar-Peled and Sabatini, ; Lim and Zoncu, This nutrient-sensing machinery regulates the mammalian target of rapamycin mTOR , a crucial kinase that acts as a hub for the control of cell growth and metabolism.

In the presence of amino acids, mTOR activity stimulates protein translation and promotes cell growth, while inhibiting autophagy and suppressing TFEB activity. When amino acids become scarce, mTOR is inactivated. This relieves its inhibitory effect on autophagy and TFEB-dependent lysosomal biogenesis, thus promoting amino acid recycling Figure 1 ; Settembre et al.

Interestingly, mTOR also regulates the efflux of essential amino acids from lysosomes. During amino acid starvation, mTOR inhibition leads to the selective sequestration of essential amino acids within lysosomes as a preservation mechanism. On the other hand, non-essential amino acids such as glutamine and glutamate are not affected by mTOR and are thus still released under starvation conditions Abu-Remaileh et al.

As a result, they could potentially be imported into mitochondria and used as an energy source. In addition to this direct metabolic regulation, mTOR inhibition also relieves its inhibition of TFEB which, in turn, stimulates lysosomal biogenesis to help with the increased delivery of material to lysosomes caused by increased autophagy. The metabolic changes caused by amino acid starvation also extend to mitochondria.

Starvation promotes mitochondrial elongation and connectivity, and improves mitochondrial bioenergetics through ATP synthase assembly and changes in inner mitochondrial membrane cristae organization Gomes et al. While mitochondrial elongation is caused by the PKA-dependent inhibition of DRP1, a Dynamin related GTPase required for mitochondrial fission, other changes are likely controlled more directly by amino acids.

In addition to these direct changes, the fact that TFEB stimulates mitochondrial biogenesis in addition to lysosomal biogenesis suggests that there is a coordinated metabolic program that is activated by amino acid starvation to promote cellular adaptation to metabolic stress. Interestingly, a recent study indicated that mTOR also regulates mitochondrial structure through a TFEB-independent pathway that relies on MTFP1, a mitochondrial protein promoting mitochondrial fragmentation.

In nutrient-replete cells, a key role of mTOR is to repress 4eBP, an important translation inhibitor. However, during starvation, mTOR inactivation relieves this inhibition, thereby decreasing protein translation. Overall, these studies indicate that amino acid starvation co-ordinately regulates the function of mitochondria and lysosomes. This metabolic control is driven by mTOR and TFEB, also at a more direct level by the flux of amino acids and fatty acids between the two organelles.

In the last decade, the realization that organelles interact in a close physical and functional manner has opened new research areas with important implications for our understanding of several diseases. Recent findings highlighting the physical and functional interaction between mitochondria and lysosomes suggest that this crosstalk plays a major role in metabolic regulation.

However, several key questions remain unanswered Figure 1 , boxes 1—3. First, the nature of the physical interaction between the two organelles in mammalian cells remains unknown, making it difficult to assess to which extent their functional interaction requires direct physical contact. Second, both mitochondria and lysosomes have independently been studied for their role in the regulation of amino acids and lipids, but how these processes are coordinated and integrated remains an open question.

Given the intimate links between mitochondria and lysosomes in disease, especially neurodegenerative diseases, these are important areas that remain to be explored. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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