UllrichcongenitalmusculardystrophyandBethlemmyopathyarecausedbymutationsincollagenVI(ColVI)genes,whichencodeanextracellularmatrixprotein;yet,mitochondriaplayamajorroleindiseasepathogenesisthroughashortcircuitcausedbyinappropriateopeningofthepermeabilitytransitionpore,ahigh-conductancechannel,whichcausesashortageinATPproduction.WefindthatmelanocytesdonotproduceColVIyettheybinditatthecellsurface,suggestingthatthisproteinmayplayatrophicroleandthatitsabsencemaycauselesionssimilartothoseseeninskeletalmuscle.WeshowthatmitochondriainmelanocytesofUllrichcongenitalmusculardystrophyandBethlemmyopathypatientsdisplayincreasedsize,reducedmatrixdensity,anddisruptedcristae,findingsthatsuggestafunctionalimpairment.Inkeepingwiththishypothesis,mitochondria(i)underwentanom-alousdepolarizationafterinhibitionoftheF-ATPsynthasewitholigomycin,and(ii)displayeddecreasedrespiratoryreservecapacity.Thenon-immunosuppressivecyclophilininhibitorNIM811preventedmitochondrialdepolarizationinresponsetooligomycininmelanocytesfrombothUllrihcongenitalmusculardystrophyandBethlemmyopathypatients,andpartiallyrestoredtherespiratoryreserveofmelanocytesfromoneBethlemmyopathypatient.TheseresultsmatchourrecentfindingsonmelanocytesfrompatientsaffectedbyDuchennemusculardystrophy(Pellegrinietal.,2013),andsuggestthatskinbiopsiesmayrepresentaminimallyinvasivetooltoinvestigatemitochondrialdysfunctionandtoevaluatedrugefficacyinColI-relatedmyopathiesandpossiblyinothermusclewastingconditionslikeagingsarcopenia.
Zulian A, Tagliavini F, Rizzo E, Pellegrini C, Sardone F, Zini N, et al. (2014). Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors. FRONTIERS IN AGING NEUROSCIENCE, 6, 1-10 [10.3389/fnagi.2014.00324].
Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors.
FALDINI, CESARE;
2014
Abstract
UllrichcongenitalmusculardystrophyandBethlemmyopathyarecausedbymutationsincollagenVI(ColVI)genes,whichencodeanextracellularmatrixprotein;yet,mitochondriaplayamajorroleindiseasepathogenesisthroughashortcircuitcausedbyinappropriateopeningofthepermeabilitytransitionpore,ahigh-conductancechannel,whichcausesashortageinATPproduction.WefindthatmelanocytesdonotproduceColVIyettheybinditatthecellsurface,suggestingthatthisproteinmayplayatrophicroleandthatitsabsencemaycauselesionssimilartothoseseeninskeletalmuscle.WeshowthatmitochondriainmelanocytesofUllrichcongenitalmusculardystrophyandBethlemmyopathypatientsdisplayincreasedsize,reducedmatrixdensity,anddisruptedcristae,findingsthatsuggestafunctionalimpairment.Inkeepingwiththishypothesis,mitochondria(i)underwentanom-alousdepolarizationafterinhibitionoftheF-ATPsynthasewitholigomycin,and(ii)displayeddecreasedrespiratoryreservecapacity.Thenon-immunosuppressivecyclophilininhibitorNIM811preventedmitochondrialdepolarizationinresponsetooligomycininmelanocytesfrombothUllrihcongenitalmusculardystrophyandBethlemmyopathypatients,andpartiallyrestoredtherespiratoryreserveofmelanocytesfromoneBethlemmyopathypatient.TheseresultsmatchourrecentfindingsonmelanocytesfrompatientsaffectedbyDuchennemusculardystrophy(Pellegrinietal.,2013),andsuggestthatskinbiopsiesmayrepresentaminimallyinvasivetooltoinvestigatemitochondrialdysfunctionandtoevaluatedrugefficacyinColI-relatedmyopathiesandpossiblyinothermusclewastingconditionslikeagingsarcopenia.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
