Mitochondria–Lysosome Crosstalk: From Physiology to Neurodegeneration
Authors: Cláudia M. Deus, King Faisal Yambire, Paulo J. Oliveira, Nuno Raimundo
Journal: Trends in Molecular Medicine (2019)

The functions of mitochondria and lysosomes are coordinated with cellular metabolism and signaling.AMPK and mTORC1 mediate mitochondria–lysosome crosstalk.Acute and chronic mitochondrial stress has opposite effects on lysosomal biogenesis.Lysosomal storage diseases trigger repression of mitochondrial biogenesis.Mitochondria–lysosome crosstalk is impaired in neurodegenerative diseases. Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major contributors of chemical energy and building blocks. It is therefore pivotal for cellular function to coordinate the metabolic roles of mitochondria and lysosomes. However, these organelles do more than metabolism, given their function as fundamental signaling platforms in the cell that regulate many key processes such as autophagy, proliferation, and cell death. Mechanisms of crosstalk between mitochondria and lysosomes are discussed, both under physiological conditions and in diseases that affect these organelles. Cellular function requires coordination between different organelles and metabolic cues. Mitochondria and lysosomes are essential for cellular metabolism as major contributors of chemical energy and building blocks. It is therefore pivotal for cellular function to coordinate the metabolic roles of mitochondria and lysosomes. However, these organelles do more than metabolism, given their function as fundamental signaling platforms in the cell that regulate many key processes such as autophagy, proliferation, and cell death. Mechanisms of crosstalk between mitochondria and lysosomes are discussed, both under physiological conditions and in diseases that affect these organelles. Life is an elaborate system of chemical reactions which require organization. This chemistry is often compartmentalized by phases or physical barriers. Cellular organelles such as mitochondria, peroxisomes, lysosomes, and others present extreme examples of compartmentalization by containing a specific set of chemical reactions within the limits of their membranes. These organelles carry out different functions and together contribute to the survival of the cell, and eventually to its growth and division. The compartmentalization provided by organelles presents, however, a challenge to the cell: the organelles must be coordinated to ensure that the whole cell is tuned. Multicellular organisms have many different cell types, but they all have key common aspects such as the use of ATP and thioester bonds as energy currency, as well as the ability to survive different stresses (e.g., ischemia-induced hypoxia, fever-related heat shock). Cells cope with stress by triggering the appropriate responder, which triggers a carefully executed plan for adaptation and survival. One of the major stresses met by almost all cells and organisms is the availability of nutrients and energy, or lack thereof. Metabolism is a key component of stress responses because it allows redirection of fuels to generate energy (catabolism) or for conversion into building blocks (anabolism). Both branches of metabolism rely heavily on mitochondria and lysosomes, not only as providers of energy and building blocks but also as regulators of metabolic activity across the cell. Therefore, it is pivotal that mitochondria and lysosomes are effectively coordinated. The purpose of this review is to discuss recent advances in understanding the communication between mitochondria and lysosomes, how this crosstalk contributes to physiological cell function, and how perturbations in mitochondria–lysosome crosstalk are involved in pathology. Although the outcomes are conserved between higher and lower Eukarya, the underlying mechanisms differ significantly. We therefore focus on mammalian mitochondria–lysosome crosstalk. To coordinate the function of different organelles, several aspects need to be controlled: how and when the organelle is built (biogenesis), where it is positioned, which functions it performs, and how it is removed. Reciprocally, the organelle must inform the cell of its status and needs, and the cell needs to react accordingly. The kinetics of any of these aspects is pivotal because the cell may need to respond to a particular stress within seconds or minutes (e.g., hypoxia, nutrient depletion, exercise, activation of immune cells) or may need to remain under stress conditions for a long time (e.g., infection, genetic defects in an organelle). Organelle biogenesis is often used both in reference to the transcriptional programs that trigger the expression of the complete repertoire of an organelle proteome, as well as to the mechanisms leading to the import and assembly of those proteins into macromolecular complexes in the organelle. In this review, organelle biogenesis refers to the transcriptional programs. The key aspects of mitochondrial and lysosomal biogenesis are described in Box 1, but it is important to note that several transcription factors seem to be able to trigger both mitochondrial and lysosomal biogenesis.Box 1Mitochondrial and Lysosomal BiogenesisThe transcriptional programs of organelle biogenesis comprise coordinated transcription of the complete set of genes necessary to make a functional new organelle. These are complex programs that involve ∼600 genes for lysosomes [98Palmieri M. et al.Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways.Hum. Mol. Genet. 2011; 20: 3852-3866Crossref PubMed Scopus (325) Google Scholar] and ∼1000–1500 genes for mitochondria [99Pagliarini D.J. et al.A mitochondrial protein compendium elucidates complex I disease biology.Cell. 2008; 134: 112-123Abstract Full Text Full Text PDF PubMed Scopus (1194) Google Scholar]. Specific transcription factors that have cis-elements in the promoters or enhancers of these genes drive their coordinated expression.Multiple transcription factors promote mitochondrial biogenesis, of which the nuclear respiratory factor 1 (NRF1), peroxisome proliferator-activated receptor α (PPAR-α), PPAR-β/δ, PPAR-γ, estrogen-related receptor α (ERRα), ERRγ, Myc, and nuclear respiratory factor 2 (known as GA-binding protein transcription factor, composed of α and β subunits, GABPA and GABPB; NRF2 should be avoided because this is often used as a reference to an unrelated transcription factor, nuclear factor erythroid 2-like 2, NFE2L2, which coordinates antioxidant responses) are pivotal examples. Many other transcription factors have also been implicated in the expression of some mitochondrial genes, but it is less clear whether they can coordinate the entire program of mitochondrial biogenesis, such as SP1, MEF2, CREB, FoxO, YY-1, and E2F1, among others. The transcription factors promoting mitochondrial biogenesis often work in association with the transcriptional coactivators PGC-1α or PGC-1β. A comprehensive discussion of the mechanisms of mitochondrial biogenesis is outside of the scope of this article and has been summarized elsewhere [100Quiros P.M. et al.Mitonuclear communication in homeostasis and stress.Nat. Rev. Mol. Cell Biol. 2016; 17: 213-226Crossref PubMed Scopus (192) Google Scholar]. Notably, although many transcription factors are known to activate mitochondrial biogenesis, two transcription factors were recently found to repress biogenesis. KLF2 and ETV1 are able to silence the expression of nucleus-encoded mitochondrial genes, and their overexpression results in impairment of the mitochondrial respiratory chain [42Yambire K.F. et al.Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases.eLife. 2019; 8: e39598Crossref PubMed Scopus (1) Google Scholar].The coordinated expression of lysosomal genes (nucleus-encoded genes which encode lysosomal proteins) is ensured by the microphthalmia transcription factors TFEB, MITF, TFE3, and TFEC [101Sardiello M. et al.A gene network regulating lysosomal biogenesis and function.Science. 2009; 325: 473-477Crossref PubMed Scopus (943) Google Scholar]. The coactivator ACSS2 cooperates with TFEB to promote lysosomal biogenesis [102Li X. et al.Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy.Mol. Cell. 2017; 66: 684-697Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Other transcription factors can also induce the expression of lysosomal genes, such as CREB, FoxO, PPARα, and E2F1 [103Fullgrabe J. et al.Transcriptional regulation of mammalian autophagy at a glance.J. Cell Sci. 2016; 129: 3059-3066Crossref PubMed Scopus (35) Google Scholar]. Several autophagy-related genes are under the same regulatory circuits as lysosomal genes. As in the case of mitochondrial biogenesis, there are negative regulators of the transcriptional program of lysosomal/autophagy biogenesis, such as the farnesoid X receptor (FXR) and the bromodomain protein BRD4 [103Fullgrabe J. et al.Transcriptional regulation of mammalian autophagy at a glance.J. Cell Sci. 2016; 129: 3059-3066Crossref PubMed Scopus (35) Google Scholar].Interestingly, several transcription factors can influence both mitochondrial and lysosomal/autophagy biogenesis, such as CREB, FoxO, and E2F1. Although it remains unclear whether these transcription factors can trigger both programs simultaneously, there is evidence that TFEB and TFE3 can also promote the transcriptional program of mitochondrial biogenesis in cell lines [101Sardiello M. et al.A gene network regulating lysosomal biogenesis and function.Science. 2009; 325: 473-477Crossref PubMed Scopus (943) Google Scholar] and in vivo [104Pastore N. et al.TFE3 regulates whole-body energy metabolism in cooperation with TFEB.EMBO Mol. Med. 2017; 9: 605-621Crossref PubMed Scopus (16) Google Scholar], possibly involving induction of the coactivator PGC1α, a major coordinator of mitochondrial (and peroxisomal) biogenesis [105Wu Z. et al.Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (2571) Google Scholar]. Therefore, TFE3 may represent a mechanism that coordinates the biogenesis of mitochondria and lysosomes (and possibly of peroxisomes). The transcriptional programs of organelle biogenesis comprise coordinated transcription of the complete set of genes necessary to make a functional new organelle. These are complex programs that involve ∼600 genes for lysosomes [98Palmieri M. et al.Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways.Hum. Mol. Genet. 2011; 20: 3852-3866Crossref PubMed Scopus (325) Google Scholar] and ∼1000–1500 genes for mitochondria [99Pagliarini D.J. et al.A mitochondrial protein compendium elucidates complex I disease biology.Cell. 2008; 134: 112-123Abstract Full Text Full Text PDF PubMed Scopus (1194) Google Scholar]. Specific transcription factors that have cis-elements in the promoters or enhancers of these genes drive their coordinated expression. Multiple transcription factors promote mitochondrial biogenesis, of which the nuclear respiratory factor 1 (NRF1), peroxisome proliferator-activated receptor α (PPAR-α), PPAR-β/δ, PPAR-γ, estrogen-related receptor α (ERRα), ERRγ, Myc, and nuclear respiratory factor 2 (known as GA-binding protein transcription factor, composed of α and β subunits, GABPA and GABPB; NRF2 should be avoided because this is often used as a reference to an unrelated transcription factor, nuclear factor erythroid 2-like 2, NFE2L2, which coordinates antioxidant responses) are pivotal examples. Many other transcription factors have also been implicated in the expression of some mitochondrial genes, but it is less clear whether they can coordinate the entire program of mitochondrial biogenesis, such as SP1, MEF2, CREB, FoxO, YY-1, and E2F1, among others. The transcription factors promoting mitochondrial biogenesis often work in association with the transcriptional coactivators PGC-1α or PGC-1β. A comprehensive discussion of the mechanisms of mitochondrial biogenesis is outside of the scope of this article and has been summarized elsewhere [100Quiros P.M. et al.Mitonuclear communication in homeostasis and stress.Nat. Rev. Mol. Cell Biol. 2016; 17: 213-226Crossref PubMed Scopus (192) Google Scholar]. Notably, although many transcription factors are known to activate mitochondrial biogenesis, two transcription factors were recently found to repress biogenesis. KLF2 and ETV1 are able to silence the expression of nucleus-encoded mitochondrial genes, and their overexpression results in impairment of the mitochondrial respiratory chain [42Yambire K.F. et al.Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases.eLife. 2019; 8: e39598Crossref PubMed Scopus (1) Google Scholar]. The coordinated expression of lysosomal genes (nucleus-encoded genes which encode lysosomal proteins) is ensured by the microphthalmia transcription factors TFEB, MITF, TFE3, and TFEC [101Sardiello M. et al.A gene network regulating lysosomal biogenesis and function.Science. 2009; 325: 473-477Crossref PubMed Scopus (943) Google Scholar]. The coactivator ACSS2 cooperates with TFEB to promote lysosomal biogenesis [102Li X. et al.Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy.Mol. Cell. 2017; 66: 684-697Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Other transcription factors can also induce the expression of lysosomal genes, such as CREB, FoxO, PPARα, and E2F1 [103Fullgrabe J. et al.Transcriptional regulation of mammalian autophagy at a glance.J. Cell Sci. 2016; 129: 3059-3066Crossref PubMed Scopus (35) Google Scholar]. Several autophagy-related genes are under the same regulatory circuits as lysosomal genes. As in the case of mitochondrial biogenesis, there are negative regulators of the transcriptional program of lysosomal/autophagy biogenesis, such as the farnesoid X receptor (FXR) and the bromodomain protein BRD4 [103Fullgrabe J. et al.Transcriptional regulation of mammalian autophagy at a glance.J. Cell Sci. 2016; 129: 3059-3066Crossref PubMed Scopus (35) Google Scholar]. Interestingly, several transcription factors can influence both mitochondrial and lysosomal/autophagy biogenesis, such as CREB, FoxO, and E2F1. Although it remains unclear whether these transcription factors can trigger both programs simultaneously, there is evidence that TFEB and TFE3 can also promote the transcriptional program of mitochondrial biogenesis in cell lines [101Sardiello M. et al.A gene network regulating lysosomal biogenesis and function.Science. 2009; 325: 473-477Crossref PubMed Scopus (943) Google Scholar] and in vivo [104Pastore N. et al.TFE3 regulates whole-body energy metabolism in cooperation with TFEB.EMBO Mol. Med. 2017; 9: 605-621Crossref PubMed Scopus (16) Google Scholar], possibly involving induction of the coactivator PGC1α, a major coordinator of mitochondrial (and peroxisomal) biogenesis [105Wu Z. et al.Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124Abstract Full Text Full Text PDF PubMed Scopus (2571) Google Scholar]. Therefore, TFE3 may represent a mechanism that coordinates the biogenesis of mitochondria and lysosomes (and possibly of peroxisomes). The positioning of the organelles is an important but often overlooked issue. There are several populations of lysosomes in the cell, and their positions relative to the plasma membrane and the nucleus are important to their specific functions [1Korolchuk V.I. et al.Lysosomal positioning coordinates cellular nutrient responses.Nat. Cell. Biol. 2011; 13: 453-460Crossref PubMed Scopus (393) Google Scholar]. Mitochondria are, under normal conditions, spread around the cell in a relatively uniform manner, but rapidly relocate to the perinuclear region at the onset of different stresses [2De Paepe B. et al.Fluorescence imaging of mitochondria in cultured skin fibroblasts: a useful method for the detection of oxidative phosphorylation defects.Pediatr. 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These are often referred to as 'retrograde' signaling because they originate in the organelles and eventually affect the nucleus, as opposed to 'anterograde' signaling in which the nuclear gene expression machinery modulates the function of the organelle [5Raimundo N. et al.Mitochondrial signaling.in: Hockenberry D.M. Mitochondria and Cell Death. Humana Press, 2015: 169-184Google Scholar]. For example, lysosomes can retain calcium (Ca2+), iron, cholesterol, or sphingomyelin, and each of these can be sensed by the cell [6Perera R.M. Zoncu R. The lysosome as a regulatory hub.Annu. Rev. Cell. Dev. Biol. 2016; 32: 223-253Crossref PubMed Google Scholar]. Mitochondria can relay stress to the rest of the cell by increasing/decreasing their Ca2+ uptake, slowing down protein import, releasing metabolites, reactive oxygen species (ROS), and vesicles, as well as by exporting peptides (such as the case of ClpP- and HAF-1-dependent peptide export in C. elegans under mitochondrial proteotoxic stress and MOTS-c export in mammals) or mitochondrial DNA (mtDNA) [7Pellegrino M.W. et al.Signaling the mitochondrial unfolded protein response.Biochim. Biophys. Acta. 2013; 1833: 410-416Crossref PubMed Scopus (176) Google Scholar,8West A.P. et al.Mitochondrial DNA stress primes the antiviral innate immune response.Nature. 2015; 520: 553-557Crossref PubMed Scopus (89) Google Scholar]. As with any other signaling paradigm, organelle retrograde signaling depends on key properties of each signal: trigger, intensity, frequency, and duration. The duration of the signal is a fundamental aspect of signaling because the responses to acute and chronic organelle stress may be remarkably different, at least for mitochondria [9Raimundo N. Mitochondrial pathology: stress signals from the energy factory.Trends Mol. Med. 2014; 20: 282-292Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar]. The major determinants of the duration of a signal are its trigger and its termination. Although on some occasions cessation of the stress trigger (e.g., normoxia after hypoxic conditions) is sufficient to remove the stress signal, the termination of an organelle stress signal can often only be achieved by removal of the perturbed organelle. The removal of damaged organelles is pivotal for the maintenance of healthy organellar function. There are therefore strategies in place to recognize and eliminate the damaged organelles, typically by selective autophagy of mitochondria (mitophagy) or lysosomes (lysophagy). The manner in which the defective organelles are recognized differs between mitochondria and lysosomes. The major 'red flag' for mitochondria seems to be their depolarization, which by diverse mechanisms results in ubiquitination of the outer membrane, recruitment of mitophagy receptors, and delivery of mitochondria-containing autophagosomes to the lysosome for degradation [10Youle R.J. Narendra D.P. Mechanisms of mitophagy.Nat. Rev. Mol. Cell. Biol. 2011; 12: 9-14Crossref PubMed Scopus (1490) Google Scholar]. For lysosomes, the main event leading to their demise seems to be membrane rupture, which results in the exposure of parts of the lysosomal glycocalyx that are recognized by the galectin family of proteins, which then trigger the selective autophagy of the lysosomes that are ruptured [11Jia J. et al.Galectins control mTOR in response to endomembrane damage.Mol. Cell. 2018; 70: 120-135Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. The detailed mechanisms of mitophagy and lysophagy are comprehensively discussed in recent reviews. The interdependence of mitochondria and lysosomes is underscored by many lines of evidence obtained from cells with mitochondrial malfunction. For example, mouse embryonic fibroblasts lacking AIFM1 (apoptosis-inducible factor), that is required for respiratory chain function, OPA1, that is required for mitochondrial fusion, or PINK1, that is involved in quality control of the respiratory chain and mitophagy, show lysosomal impairment [12Demers-Lamarche J. et al.Loss of mitochondrial function impairs lysosomes.J. Biol. Chem. 2016; 291: 10263-10276Crossref PubMed Scopus (57) Google Scholar]. This is evidenced by enlargement of lysosomal (LAMP1-positive) vesicles, which become nonacidic and lose their hydrolytic activity [12Demers-Lamarche J. et al.Loss of mitochondrial function impairs lysosomes.J. Biol. Chem. 2016; 291: 10263-10276Crossref PubMed Scopus (57) Google Scholar]. The detrimental effect of mitochondrial dysfunction on lysosomes is constant across different cell types in vitro (e.g., clonal cell lines) and in vivo (e.g., activation of effector T cells, Huntington's disease heart) [13Baixauli F. et al.Mitochondrial respiration controls lysosomal function during inflammatory T cell responses.Cell Metab. 2015; 22: 485-498Abstract Full Text Full Text PDF PubMed Google Scholar, 14Fernandez-Mosquera L. et al.Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis.Autophagy. 2019; 15: 1572-1591Crossref PubMed Scopus (3) Google Scholar, 15Joshi A.U. et al.Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington's disease.J. Mol. Cell Cardiol. 2019; 127: 125-133Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16Padman B.S. et al.The protonophore CCCP interferes with lysosomal degradation of autophagic cargo in yeast and mammalian cells.Autophagy. 2013; 9: 1862-1875Crossref PubMed Scopus (0) Google Scholar]. Importantly, this effect does not seem to be related to decreased ATP availability [12Demers-Lamarche J. et al.Loss of mitochondrial function impairs lysosomes.J. Biol. Chem. 2016; 291: 10263-10276Crossref PubMed Scopus (57) Google Scholar, 13Baixauli F. et al.Mitochondrial respiration controls lysosomal function during inflammatory T cell responses.Cell Metab. 2015; 22: 485-498Abstract Full Text Full Text PDF PubMed Google Scholar, 14Fernandez-Mosquera L. et al.Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis.Autophagy. 2019; 15: 1572-1591Crossref PubMed Scopus (3) Google Scholar]. As mentioned above, defective lysosomes are sensed by the rest of the cell. A common response in lysosomal storage diseases is the increase in lysosomal biogenesis. A similar paradigm is observed when mitochondrial dysfunction impairs lysosomal function: TFEB (transcription factor EB) and other microphthalmia family transcription factors are activated to promote an increase in lysosomal biogenesis [13Baixauli F. et al.Mitochondrial respiration controls lysosomal function during inflammatory T cell responses.Cell Metab. 2015; 22: 485-498Abstract Full Text Full Text PDF PubMed Google Scholar,17Fernandez-Mosquera L. et al.Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.Sci. Rep. 2017; 7: 45076Crossref PubMed Scopus (0) Google Scholar, 18Ivankovic D. et al.Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.J. Neurochem. 2016; 136: 388-402Crossref PubMed Google Scholar, 19Nezich C.L. et al.MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5.J. Cell Biol. 2015; 210: 435-450Crossref PubMed Google Scholar]. Interestingly, however, activation of lysosomal biogenesis occurs in acute mitochondrial stress, but not in chronic mitochondrial stress [17Fernandez-Mosquera L. et al.Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.Sci. Rep. 2017; 7: 45076Crossref PubMed Scopus (0) Google Scholar]. This was observed in pharmacologic models of mitochondrial respiratory chain inhibition in cultured cells, in which TFEB activity was high in the first hours of respiratory chain inhibition, but eventually returned to basal levels, or is actively inhibited when the inhibition persisted over 24 h [17Fernandez-Mosquera L. et al.Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.Sci. Rep. 2017; 7: 45076Crossref PubMed Scopus (0) Google Scholar]. However, in T cells lacking the mitochondrial transcription factor A (TFAM) protein, that is essential for the maintenance, transcription, and replication of mtDNA, lysosomal biogenesis was upregulated [13Baixauli F. et al.Mitochondrial respiration controls lysosomal function during inflammatory T cell responses.Cell Metab. 2015; 22: 485-498Abstract Full Text Full Text PDF PubMed Google Scholar]. Nevertheless, it remains to be determined whether this response is TFEB-dependent, and what its functional role is, given that the lysosomes in Tfam−/− T cells were still dysfunctional [13Baixauli F. et al.Mitochondrial respiration controls lysosomal function during inflammatory T cell responses.Cell Metab. 2015; 22: 485-498Abstract Full Text Full Text PDF PubMed Google Scholar]. Furthermore, cells with chronic defects in the respiratory chain are not able to trigger lysosomal biogenesis even when using classic lysosomal biogenesis-stimulating conditions such as amino acid starvation or mTORC1 inhibition [14Fernandez-Mosquera L. et al.Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis.Autophagy. 2019; 15: 1572-1591Crossref PubMed Scopus (3) Google Scholar]. Considering the biogenesis and function of lysosomes during acute and chronic mitochondrial stress, a general picture emerges in which acute mitochondrial stress gears the cells to activate autophagy and lysosomal biogenesis, whereas under chronic stress lysosomal biogenesis is shut down and autophagy is inhibited. This can be interpreted that, under acute mitochondrial stress, the cell triggers programs that ultimately result in the elimination of the defective mitochondria, first by stimulating autophagosome formation, which promotes mitophagy, and then by ensuring that the capacity for autophagosome degradation is increased by building more lysosomes. However, should this program occur indefinitely, the cell would eventually run out of mitochondria, which would constitute a major threat to the life of most cell types. Thus, after a period in which the 'clean-up' mode is on, the cell prefers to shut down the degradation of mitochondria by inhibiting both lysosomal function and autophagosome formation – it is better to live with defective mitochondria, that are unable to efficiently carry out respiration and oxidative phosphorylation, than with no mitochondria, which would irreversibly impair the synthesis of phospholipids, heme, and Fe–S clusters. The mechanisms that underlie the effects of mitochondrial deficiency on lysosomal biogenesis and function have only recently been uncovered. Lysosomal biogenesis triggered by acute mitochondrial stress requires the function of the microphthalmia transcription factors, particularly TFEB and MITF, although exactly which ones are necessary is likely to be dependent on the cell type [13Baixauli F. et al.Mitochondrial respiration controls lysosomal function during inflammatory T cell responses.Cell Metab. 2015; 22: 485-498Abstract Full Text Full Text PDF PubMed Google Scholar,17Fernandez-Mosquera L. et al.Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.Sci. Rep. 2017; 7: 45076Crossref PubMed Scopus (0) Google Scholar, 18Ivankovic D. et al.Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.J. Neurochem. 2016; 136: 388-402Crossref PubMed Google Scholar, 19Nezich C.L. et al.MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5.J. Cell Biol. 2015; 210: 435-450Crossref PubMed Google Scholar]. The activation of TFEB signaling and lysosomal biogenesis is dependent on AMPK (AMP-dependent protein kinase) activation, both under mitochondrial stress in cultured cells [17Fernandez-Mosquera L. et al.Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.Sci. Rep. 2017; 7: 45076Crossref PubMed Scopus (0) Google Scholar] as well as under physiological conditions in vivo [20Young N.P. et al.AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes.Genes Dev. 2016; 30: 535-552Crossref PubMed Scopus (37) Google Scholar]. AMPK is a sensor of the energy charge and other stress signals [21Garcia D. Shaw R.J. AMPK: mechanisms of cellular energy Sensing and restoration of metabolic balance.Mol. Cell. 2017; 66: 789-800Abstract Full Text Full Text PDF PubMed Google Scholar], and is the grand regulator of metabolism that activates key catabolic pathways while inhibiting anabolism. It functions almost as the counterbalance to mTORC1, the kinase that coordinates most anabolic pathways. The interplay between AMPK and mTORC1, and a brief int