It All Comes Down to the Mitochondria
Iwasreallystruckbythisrecentpaper,becauseitgetsataproblemthatyou’dthinkwouldhavebeenworkedoutbynow:whatistherealbiochemicaloriginofthe“tiredandneedtosleep”feeling,anyway?Therehavebeenallsortsofchangesnotedatthecellularlevel,butthewholeareahassufferedfromanunshakeable“chickenortheegg”problem(whichisacommonfeatureofalotofbiomedicalquestions,honestly).Inthiscase,arethesechangesinmetabolites,cellularbehavior,neuronalfiringpatternsandalltherestofitthesignalsthattellyouthatyouneedsleep?Oraretheyjustthingsthatarebroughtonbytheneedforsleep,andthusdownstreamofsomethingelse?Putmoresuccinctly,arethesethingscausesorconsequences?Itcanberidiculouslyhardtoanswerthatsortofquestion,andforevidenceIwillreferencethequestionofwhetheramyloiddepositsgiveyouAlzheimer’sdiseaseorwhetherAlzheimer’sdiseasegivesyouamyloiddeposits.
Alotofpainstakingworkovertheyearsinfruitflies(Drosophila)haspointedtothedorsalfan-shapedbody(andparticularlyneuronsthatprojecttoit)astheimportantsleep-regulatingcenter.Thenewpaperlinkedabovelooksatsuchneuronsafterextendedsleepdeprivationinfliesanddoessingle-cellanalysesontheseneurons.122genetranscriptswereelevatedundertheseconditions,withclustersaroundtwoprocesses(mitochondrialfunctionandsynaptictransmission)standingout.Thattiesinwithearlierreportsaboutmitochondrialactivitybeingtiedtosleepfunctioninthesecells,andacloseexaminationofthecellsshowedthatassleepdeprivationincreasesthereareincreasedsignsofmitochondrialfragmentation,mitophagy,andoutrightcontactsbetweenmitochondriaandtheendoplasmicreticulum(thelastofwhichisthoughttobeawaytotakeonfreshlipidsasexistingonesbecomedamagedbyreactiveoxygenspecies).
Theauthorsgoontodoseveralexperimentsalteringelectrontransportinthemitochondria,andshowthattheseseemdirectlyrelatedtothesleep-inducingfunctionsoftheseneurons.Sleepdeprivationwithnonstopactivityofthemitochondriaseemtoinducemoremitochondrialfissionandrecycling,andthevariousmodificationsallpointinthedirectionofabuildupofmitochondrialelectronsurplusasthefundamentalinduceroftheneedtosleep.Thehypothesisisthataerobicrespirationitselfcomeswiththetradeoffofarequiredsleepstateinordertocatchupandrestoremitochondrialfunctioninthenervoussystem,whichsimplycannotkeepfunctioningwithoutabreak.Theauthorsnotethatacommonsymptomofhumanmitochondrialdysfunctionisamassivefeelingoftiredness(andalackof“restorativesleep”tofixit,Iwouldadd).
Thisalsostronglysuggeststhatsleepandhungerarebothtiedtomitochondrialfunctionandenergybalance(thelatterwasalreadyprettyclear!),andthataerobicorganismsareconstantlyadjustingforbothfuelingtheirmitochondriaandgivingthem(especiallytheonesinthecentralnervoussystem)somedowntimeforrepairandrecovery.Astheauthorssay,rathereloquently,“electronsflowthroughtherespiratorychainsoftherespectivefeedbackcontrollerslikesandinthehourglassthatdetermineswhenbalancemustberestored”.Therecouldwellbemanyotherfunctionsthathavesincejoinedinwiththesleepcycle(suchasmemoryconsolidation),buttheauthorshypothesizethatmitochondrialfunctionistheprocessthatunderliesallofthem.Ifyouneedoxygen,thenyouneedsleep!
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