calcium concentrations in the millimolar range are found in the extracellular space and in the lumen of the er , the golgi apparatus , and acidic organelles , whereas the cytosolic concentration of the ion is kept low ( typically 100 nm ) . mcss , in particular between the er and pm , or the er and mitochondria , have been implicated in the regulation of direct calcium transfer between organelles . this mechanism has the advantage of maximizing the efficiency of calcium signaling and interorganellar exchange , while avoiding excessive or prolonged changes in the overall concentration of cytosolic calcium , which in turn could be detrimental for the cell . in all cells , a store - operated calcium entry pathway ( soce ) functions at er - pm mcss to efficiently refill er stores upon calcium release , typically caused by opening of inositol-1,4,5-triphosphate receptors ( ins(1,4,5)p3rs ) . the transmembrane er proteins stim sense the depletion of calcium in the er and oligomerize , translocating to er - pm contact sites and activating the crac / orai1 ca channels on the pm . in this manner , calcium depletion in the er recalls the ion available in the extracellular space , which enters the cytosol and can reload the er stores via the sarcoplasmic / endoplasmic reticulum ca atpases . in muscle cells an additional er - pm mcss is found that comprises voltage - gated calcium channels on the pm , functionally connected with ryanodine receptors ( ryrs ) on the er , so that opening of the former also results in activation of the latter to maximize cytosolic calcium influx during excitation - contraction coupling . on the other hand , mcss between the er and mitochondria , also known as mitochondria - associated - membranes ( mams ) are mainly implicated in spatially restricting and buffering the calcium fluxes triggered by opening of ins(1,4,5)p3rs or ryrs on the er membrane . indeed , close juxtaposition between the 2 compartments generates cytosolic microdomains , where high calcium concentrations are achieved , and is required for the ability of mitochondria to efficiently uptake the calcium released from the er by the low affinity mitochondrial calcium uniporter ( mcu ) . the correct functioning of this system and the interorganellar distance are crucial for mitochondrial calcium homeostasis and appear necessary both to regulate atp production , which depends on several ca dependent metabolic enzymes in the mitochondrial matrix , and to avoid ca overload in the mitochondria , which instead promotes apoptosis . a role in the modulation of calcium fluxes and/or signaling has also been postulated for mcss between er and late endosomes / lysosomes ( le / lys ) . indeed , both lysosomes and lros are acidic calcium stores and lysosomes have been shown to release calcium upon different stimuli , by means of ca permeable channels , including 2 pore channels ( tpc ) , transient receptor potential mucolipin ( trpml ) channels , and ins(1,4,5)p3rs / ryrs . this in turn can evoke and/or amplify er - dependent ca release , with implications for calcium oscillations in different systems . moreover , defective lysosomal calcium homeostasis has been associated to endocytic and lysosomal dysfunction , abnormalities in membrane traffic , and lysosomal storage diseases . among lros , melanosomes contain high calcium concentrations and are thought to participate in calcium homeostasis and/or signaling , since melanin is able to bind and buffer the ion , likely functioning as an intracellular calcium reservoir . the melanosome - mitochondrion juxtaposition could be involved in buffering and/or sensing of calcium possibly released by melanosomes during maturation , controlling the local concentration of the ion and evoking further signals between the 2 organelles , required for proper melanosome biogenesis . the synthesis of membrane lipids takes place primarily in the er ; however , specific biosynthetic reactions are performed on other organelles , such as the golgi apparatus and the mitochondria . thus , either vesicular or non - vesicular transport is necessary to appropriately distribute lipids to the different subcellular compartments . mcss play an important role in the regulation of lipid homeostasis by their ability to mediate non - vesicular lipid transfer among distinct compartments through the action of lipid - transport proteins ( ltps ) . a number of ltps and their modes of action have being identified , including oxysterol - binding protein ( osbp ) and osbp - related proteins ( orp ) , operating at the er - golgi and er - pm interface , and implicated in the exchange and metabolism of sterols and phosphoinositides ; the ceramide - transfer protein cert and the glucosylceramide - transfer protein fapp2 , operating non - vesicular transport at the er - golgi and intra - golgi ( cis - trans ) contact sites , respectively ; the extended synaptotagmins ( known as tricalbins in yeast ) , functioning as er pm tethers and most likely implicated in ( glycerophospho ) lipid transfer ; and possibly in yeast the er - mitochondria encounter structure ( ermes ) complex , an er  mitochondrial tether , comprising several subunits containing lipid - binding domains . sterol - binding proteins have been identified on le / lys as well , however at this location they appear to function mostly as lipid sensors and scaffold proteins , rather than lipid transfer effectors ( see below ) . nevertheless , melanosome - mitochondrion contacts may serve to control the quality and quantity of lipids on maturing melanosomes , regulating physical properties and abundance of their membranes , and the formation of specialized domains necessary for membrane traffic processes , such as the intralumenal sorting and processing of the structural protein pmel17 . along the same line , mitochondria have been reported to supply membranes to forming autophagosomes , which could originate from the er at mams . melanosome biogenesis might share molecular mechanisms with autophagy , since genes involved in the autophagic process were identified in a screening for novel pathways involved in melanogenesis . thus , by means of mcss , mitochondria could provide melanosomes with membranes or other components required for the shape and size changes occurring during their maturation . interestingly , the small gtpase rab32 , which localizes to both the er and mitochondria , and regulates the properties of mams , is also involved in the formation of autophagosomes , and in melanosome biogenesis and transport , thus representing a potential candidate regulator of this crosstalk . it is becoming evident that at least some mcss function as signaling hubs , by facilitating the scaffolding of signaling protein complexes and allowing the carry out of catalytic reactions , either in cis or in trans , with enzyme and substrate located on the same or on juxtaposed organelles , respectively . for instance , some orps have been shown to act as protein scaffolds , coordinating lipid sensing and metabolism with cell signaling and membrane traffic events , and the protein kinase mtorc2 and the lipid / protein phosphatase pten localize to the er and operate in cis at mams . moreover , internalized egfr on endosomes , and in particular on the limiting membrane of multivesicular bodies ( mvb ) , becomes dephosphorylated in trans , by means of the protein tyrosine phosphatase 1b ( ptp1b ) located on er membranes at mcss between the 2 compartments . close juxtaposition between the er and mvbs allows enzyme and substrate to interact and might also be implicated in the subsequent fate of the receptor , such as sequestration in intra - luminal vesicles ( ilv ) and lysosomal degradation . likewise , the er - pm juxtaposition may allow the regulation of phosphatidylinositol 4-phosphate ( pi4p ) levels at the cell surface , by means of the er - localized pip phosphatase sac1 , although recent evidence supports an alternative mechanism . similarly , the melanosome - mitochondrion interaction might play a role in the assembly and modulation of signaling pathways and membrane traffic events necessary for melanogenesis . of note , melanosomal membranes carry a peculiar type of intracellular g - protein - coupled receptor ( gpcr ) , named oa1 , which is involved in melanosome biogenesis and transport , and appears functionally associated to melanosome - mitochondrion contacts . thus , the oa1 gpcr might promote the formation of mcss between the 2 organelles , either directly acting as a tether or , most likely , indirectly by means of its signaling cascade or by its ability to stimulate the melanogenic process . er - mitochondria mcss have been shown to play a role in mitochondrial fusion - fission and overall motility . these processes are crucial for mitochondrial biogenesis , distribution , and function , and their alteration results in inherited or age - related neurodegenerative diseases . mitochondria continuously fuse and divide , by means of pro - fusion ( mfn 1 and 2 , and opa1 , on the mitochondrial outer and inner membrane , respectively ) and pro - fission ( drp1 ) proteins . they are also highly dynamic and move bidirectionally along microtubules , by exploiting the mitochondrial gtp - ase miro and its effector milton to recruit kinesin 1 and determine the prevalence of peripheral vs. centripetal organelle transport . the er - mitochondria juxtaposition appears intertwined with these processes , since the pro - fission machinery is recruited and operates at sites where er tubules contact mitochondria , and components of the pro - fusion machinery , namely mfn 1 or 2 on the mitochondrial side and mfn 2 on the er , have been implicated in the interorganellar tethering . moreover , mfn 2 appears directly required for transport of axonal mitochondria by interacting with the miro / milton complex and affecting both kinesin and dynein - based transport . despite both mitochondria and the er are highly motile organelles , they remain linked even as they move along microtubules . the maintenance of interorganellar contacts during microtubule - based motility is also a feature of endosomes , which mature and move while they remain bound to the er . in the latter case , ltps appear implicated in orchestrating membrane lipid content with organelle motility and connection with other compartments . on le , the rab7 effector orpl1 is required for dynein activity upon recruitment by the rilp / dynactin complex . orpl1 is also a cholesterol sensor , and in low cholesterol conditions it undergoes a conformational change that induces er - le mcss , displacing the dynein / dynactin complex from rilp and leading to peripheral le distribution . similarly , the endosomal cholesterol - transfer proteins stard3 and stard3nl generate mcss between les and the er and appear implicated in endosome morphology and dynamics , independently on orpl1 and ptp1b . in either case , it is not known whether sterol exchange occurs at the interorganellar junctions . as mitochondria , the er , and endosomes , melanosomes are highly motile organelles , traveling along microtubules and actin filaments . mitochondria and melanosomes might cope with their interactions during movement by means of dynamic , transient contacts , in a alternatively , the organelles might be joint by more persistent and stable contacts , allowing coordinated motility and distribution . the latter possibility would be more compatible with the generation of cytosolic microdomains , allowing the localized exchange of small molecules between the 2 organelles , as in the case of calcium at the er - mitochondria juxtaposition . in addition to the regulation of calcium fluxes , another main function of mitochondria is to produce atp and both their abundance and distribution in tissues and cells correlates with energetic needs . moreover , mitochondria are able to redistribute at sites of high - energy requirement , such as neuronal , and immunological synapses , regulating their motility in response to intrinsic and extrinsic calcium concentrations . thus , mitochondria juxtaposition might be required to timely and locally supply melanosomes with the atp needed either for their movement along microtubule and actin tracks , or for melanin synthesis , or for controlling the melanosomal ph and membrane composition . the compartmentalization of biochemical functions requires the reciprocal crosstalk between organelles to maintain the cellular homeostasis and to guarantee an efficient and coordinated response to environmental changes . interorganellar mcss allow virtually any combination of membrane - bound compartments to establish a communication . the newly identified contacts between melanosomes and mitochondria demonstrate that the 2 compartments not only are coordinated at the transcriptional level , but also interact at the physical level . given the characteristics of melanosomes as models of secretory organelles , it is possible that secretory granules in neuroendocrine cells or other lros in hematopoietic cells connect with mitochondria during their biogenesis and transport . understanding the structural and functional features of these interactions is critical not only by a biological point of view , but also for the possibility that organelle biogenesis could be pharmacologically modulated by exploiting and targeting mcss . calcium concentrations in the millimolar range are found in the extracellular space and in the lumen of the er , the golgi apparatus , and acidic organelles , whereas the cytosolic concentration of the ion is kept low ( typically 100 nm ) . mcss , in particular between the er and pm , or the er and mitochondria , have been implicated in the regulation of direct calcium transfer between organelles . this mechanism has the advantage of maximizing the efficiency of calcium signaling and interorganellar exchange , while avoiding excessive or prolonged changes in the overall concentration of cytosolic calcium , which in turn could be detrimental for the cell . in all cells , a store - operated calcium entry pathway ( soce ) functions at er - pm mcss to efficiently refill er stores upon calcium release , typically caused by opening of inositol-1,4,5-triphosphate receptors ( ins(1,4,5)p3rs ) . the transmembrane er proteins stim sense the depletion of calcium in the er and oligomerize , translocating to er - pm contact sites and activating the crac / orai1 ca channels on the pm . in this manner , calcium depletion in the er recalls the ion available in the extracellular space , which enters the cytosol and can reload the er stores via the sarcoplasmic / endoplasmic reticulum ca atpases . in muscle cells an additional er - pm mcss is found that comprises voltage - gated calcium channels on the pm , functionally connected with ryanodine receptors ( ryrs ) on the er , so that opening of the former also results in activation of the latter to maximize cytosolic calcium influx during excitation - contraction coupling . on the other hand , mcss between the er and mitochondria , also known as mitochondria - associated - membranes ( mams ) are mainly implicated in spatially restricting and buffering the calcium fluxes triggered by opening of ins(1,4,5)p3rs or ryrs on the er membrane . indeed , close juxtaposition between the 2 compartments generates cytosolic microdomains , where high calcium concentrations are achieved , and is required for the ability of mitochondria to efficiently uptake the calcium released from the er by the low affinity mitochondrial calcium uniporter ( mcu ) . the correct functioning of this system and the interorganellar distance are crucial for mitochondrial calcium homeostasis and appear necessary both to regulate atp production , which depends on several ca dependent metabolic enzymes in the mitochondrial matrix , and to avoid ca overload in the mitochondria , which instead promotes apoptosis . a role in the modulation of calcium fluxes and/or signaling has also been postulated for mcss between er and late endosomes / lysosomes ( le / lys ) . indeed , both lysosomes and lros are acidic calcium stores and lysosomes have been shown to release calcium upon different stimuli , by means of ca permeable channels , including 2 pore channels ( tpc ) , transient receptor potential mucolipin ( trpml ) channels , and ins(1,4,5)p3rs / ryrs . this in turn can evoke and/or amplify er - dependent ca release , with implications for calcium oscillations in different systems . moreover , defective lysosomal calcium homeostasis has been associated to endocytic and lysosomal dysfunction , abnormalities in membrane traffic , and lysosomal storage diseases . among lros , melanosomes contain high calcium concentrations and are thought to participate in calcium homeostasis and/or signaling , since melanin is able to bind and buffer the ion , likely functioning as an intracellular calcium reservoir . the melanosome - mitochondrion juxtaposition could be involved in buffering and/or sensing of calcium possibly released by melanosomes during maturation , controlling the local concentration of the ion and evoking further signals between the 2 organelles , required for proper melanosome biogenesis . the synthesis of membrane lipids takes place primarily in the er ; however , specific biosynthetic reactions are performed on other organelles , such as the golgi apparatus and the mitochondria . thus , either vesicular or non - vesicular transport is necessary to appropriately distribute lipids to the different subcellular compartments . mcss play an important role in the regulation of lipid homeostasis by their ability to mediate non - vesicular lipid transfer among distinct compartments through the action of lipid - transport proteins ( ltps ) . a number of ltps and their modes of action have being identified , including oxysterol - binding protein ( osbp ) and osbp - related proteins ( orp ) , operating at the er - golgi and er - pm interface , and implicated in the exchange and metabolism of sterols and phosphoinositides ; the ceramide - transfer protein cert and the glucosylceramide - transfer protein fapp2 , operating non - vesicular transport at the er - golgi and intra - golgi ( cis - trans ) contact sites , respectively ; the extended synaptotagmins ( known as tricalbins in yeast ) , functioning as er  pm tethers and most likely implicated in ( glycerophospho ) lipid transfer ; and possibly in yeast the er - mitochondria encounter structure ( ermes ) complex , an er  mitochondrial tether , comprising several subunits containing lipid - binding domains . sterol - binding proteins have been identified on le / lys as well , however at this location they appear to function mostly as lipid sensors and scaffold proteins , rather than lipid transfer effectors ( see below ) . nevertheless , melanosome - mitochondrion contacts may serve to control the quality and quantity of lipids on maturing melanosomes , regulating physical properties and abundance of their membranes , and the formation of specialized domains necessary for membrane traffic processes , such as the intralumenal sorting and processing of the structural protein pmel17 . along the same line , mitochondria have been reported to supply membranes to forming autophagosomes , which could originate from the er at mams . melanosome biogenesis might share molecular mechanisms with autophagy , since genes involved in the autophagic process were identified in a screening for novel pathways involved in melanogenesis . thus , by means of mcss , mitochondria could provide melanosomes with membranes or other components required for the shape and size changes occurring during their maturation . interestingly , the small gtpase rab32 , which localizes to both the er and mitochondria , and regulates the properties of mams , is also involved in the formation of autophagosomes , and in melanosome biogenesis and transport , thus representing a potential candidate regulator of this crosstalk . it is becoming evident that at least some mcss function as signaling hubs , by facilitating the scaffolding of signaling protein complexes and allowing the carry out of catalytic reactions , either in cis or in trans , with enzyme and substrate located on the same or on juxtaposed organelles , respectively . for instance , some orps have been shown to act as protein scaffolds , coordinating lipid sensing and metabolism with cell signaling and membrane traffic events , and the protein kinase mtorc2 and the lipid / protein phosphatase pten localize to the er and operate in cis at mams . moreover , internalized egfr on endosomes , and in particular on the limiting membrane of multivesicular bodies ( mvb ) , becomes dephosphorylated in trans , by means of the protein tyrosine phosphatase 1b ( ptp1b ) located on er membranes at mcss between the 2 compartments . close juxtaposition between the er and mvbs allows enzyme and substrate to interact and might also be implicated in the subsequent fate of the receptor , such as sequestration in intra - luminal vesicles ( ilv ) and lysosomal degradation . likewise , the er - pm juxtaposition may allow the regulation of phosphatidylinositol 4-phosphate ( pi4p ) levels at the cell surface , by means of the er - localized pip phosphatase sac1 , although recent evidence supports an alternative mechanism . similarly , the melanosome - mitochondrion interaction might play a role in the assembly and modulation of signaling pathways and membrane traffic events necessary for melanogenesis . of note , melanosomal membranes carry a peculiar type of intracellular g - protein - coupled receptor ( gpcr ) , named oa1 , which is involved in melanosome biogenesis and transport , and appears functionally associated to melanosome - mitochondrion contacts . thus , the oa1 gpcr might promote the formation of mcss between the 2 organelles , either directly acting as a tether or , most likely , indirectly by means of its signaling cascade or by its ability to stimulate the melanogenic process . er - mitochondria mcss have been shown to play a role in mitochondrial fusion - fission and overall motility . these processes are crucial for mitochondrial biogenesis , distribution , and function , and their alteration results in inherited or age - related neurodegenerative diseases . mitochondria continuously fuse and divide , by means of pro - fusion ( mfn 1 and 2 , and opa1 , on the mitochondrial outer and inner membrane , respectively ) and pro - fission ( drp1 ) proteins . they are also highly dynamic and move bidirectionally along microtubules , by exploiting the mitochondrial gtp - ase miro and its effector milton to recruit kinesin 1 and determine the prevalence of peripheral vs. centripetal organelle transport . the er - mitochondria juxtaposition appears intertwined with these processes , since the pro - fission machinery is recruited and operates at sites where er tubules contact mitochondria , and components of the pro - fusion machinery , namely mfn 1 or 2 on the mitochondrial side and mfn 2 on the er , have been implicated in the interorganellar tethering . moreover , mfn 2 appears directly required for transport of axonal mitochondria by interacting with the miro / milton complex and affecting both kinesin and dynein - based transport . despite both mitochondria and the er are highly motile organelles , they remain linked even as they move along microtubules . the maintenance of interorganellar contacts during microtubule - based motility is also a feature of endosomes , which mature and move while they remain bound to the er . in the latter case , ltps appear implicated in orchestrating membrane lipid content with organelle motility and connection with other compartments . on le , the rab7 effector orpl1 is required for dynein activity upon recruitment by the rilp / dynactin complex . orpl1 is also a cholesterol sensor , and in low cholesterol conditions it undergoes a conformational change that induces er - le mcss , displacing the dynein / dynactin complex from rilp and leading to peripheral le distribution . similarly , the endosomal cholesterol - transfer proteins stard3 and stard3nl generate mcss between les and the er and appear implicated in endosome morphology and dynamics , independently on orpl1 and ptp1b . in either case , it is not known whether sterol exchange occurs at the interorganellar junctions . as mitochondria , the er , and endosomes , melanosomes are highly motile organelles , traveling along microtubules and actin filaments . mitochondria and melanosomes might cope with their interactions during movement by means of dynamic , transient contacts , in a alternatively , the organelles might be joint by more persistent and stable contacts , allowing coordinated motility and distribution . the latter possibility would be more compatible with the generation of cytosolic microdomains , allowing the localized exchange of small molecules between the 2 organelles , as in the case of calcium at the er - mitochondria juxtaposition . in addition to the regulation of calcium fluxes , another main function of mitochondria is to produce atp and both their abundance and distribution in tissues and cells correlates with energetic needs . moreover , mitochondria are able to redistribute at sites of high - energy requirement , such as neuronal , and immunological synapses , regulating their motility in response to intrinsic and extrinsic calcium concentrations . thus , mitochondria juxtaposition might be required to timely and locally supply melanosomes with the atp needed either for their movement along microtubule and actin tracks , or for melanin synthesis , or for controlling the melanosomal ph and membrane composition . the compartmentalization of biochemical functions requires the reciprocal crosstalk between organelles to maintain the cellular homeostasis and to guarantee an efficient and coordinated response to environmental changes . interorganellar mcss allow virtually any combination of membrane - bound compartments to establish a communication . the newly identified contacts between melanosomes and mitochondria demonstrate that the 2 compartments not only are coordinated at the transcriptional level , but also interact at the physical level . given the characteristics of melanosomes as models of secretory organelles , it is possible that secretory granules in neuroendocrine cells or other lros in hematopoietic cells connect with mitochondria during their biogenesis and transport . understanding the structural and functional features of these interactions is critical not only by a biological point of view , but also for the possibility that organelle biogenesis could be pharmacologically modulated by exploiting and targeting mcss .
membrane contact sites ( mcss ) allow the exchange of molecules and information between organelles , even when their membranes can not fuse directly . in recent years , a number of functions have been attributed to these contacts , highlighting their critical role in cell homeostasis . 
 although inter - organellar connections typically involve the endoplasmic reticulum ( er ) , we recently reported the presence of a novel mcss between melanosomes and mitochondria . 
 melanosome - mitochondrion contacts appear mediated by fibrillar bridges resembling the protein tethers linking mitochondria and the er , both for their ultrastructural features and the involvement of mitofusin 2 . 
 the frequency of these connections correlates spatially and timely with melanosome biogenesis , suggesting a functional link between the 2 processes and in general that organelle biogenesis in the secretory pathway requires interorganellar crosstalks at multiple steps . here , we summarize the different functions attributed to mcss , and discuss their possible relevance for the newly identified melanosome - mitochondrion liaison .