Te kikorangi metilēne me te ferroptosis: te rino, te perohāoratanga o ngā lipidi, me te mate pūtau

Ko te ferroptosis he mate pūtau nā te tūkinotanga o te kiriuhi. Ka hāoratia ngā ngako hamanga-maha o ngā kiriuhi i roto i tētahi tauhohenga mekameka, ka kore te kiriuhi e mahi, ā, ka mate te pūtau. Me whai rino taua tukanga matū. Kei taua rerenga kōrero te ariā katoa, ā, ko ngā mea katoa i tēnei tuhinga he whakamātautau i tētahi wāhanga o taua ariā.

He whāiti ake te pātai i konei: he aha te pānga o te kikorangi metilēne ki taua raupapa i ngā whakamātautau pūtau, ā, he aha rawa tā taua hua e whakaatu ai? Ko te whakautu poto, i roto i ngā rangahau taiwhanga e rua, nā te kikorangi metilēne i ngā kukūtanga nanomolar i whakaiti te perohāoratanga o ngā lipidi mitokōria, i pupuri hoki i te ora o ngā pūtau i muri i ngā whakaoho e puta ai te ferroptosis ki te kore taua matū. He nui ake te hiranga o te whakautu roa, nā te mea i whakamātauria ia hononga o te raupapa mā tētahi wawaotanga rerekē, ā, he herenga tō ia wawaotanga.

Te ferroptosis i roto i te kōwae kotahi

He wāhi ngoikore tō tētahi phospholipid kiriuhi e mau ana i tētahi hiku waikawa ngako hamanga-maha: he ngota hauwai he māmā te tango. Ina tangohia tētahi e te tuwhena, ka tāpiri te hāora ki te lipidi, ka hangaia tētahi tuwhena peroxyl lipidi, ā, ka tango taua tuwhena i te hauwai o te lipidi e whai ake ana. Ka horapa te tauhohenga i te kiriuhi, ki te kore tētahi mea e aukati.

Ko te tohu aukati matua he whākōkī e kīia ana ko GPX4, e whakamahi ana i te glutathione hei whakaheke i ngā perokita lipidi kia noho hei waipiro lipidi kore-kino. Ka whakaekea tēnei ārai e ngā whakaoho taiwhanga ki ngā wāhi kua tautuhia. Ka aukati te erastin i te whakaurunga cystine mā te pūnaha xc-minus, nā reira ka kore te pūtau e whiwhi i te cysteine hei waihanga glutathione. Ka aukati tōtika te buthionine sulfoximine i te waihangatanga glutathione. Ka tautāmi te RSL3 i te GPX4 tonu. Mā ēnei mea e toru e waiho ai ngā perokita kia kore e tangohia, engari he rerekē ngā kaupae e pāngia ana. Nō reira, kāore e tika te whakawhānui aunoa i tētahi hua nō tētahi whakaoho ki ērā atu.

He rerekē te ferroptosis i te apoptosis i runga i ngā āhuatanga e tautuhi ana i a ia. Kāore he raupapa whakahohe caspase, kāore hoki he tinana apoptosis. Ka tāmi ngā matū here-rino pērā i te deferoxamine, me ngā matū hopu-tuwhena pērā i te ferrostatin-1, i tēnei mate. Ko tēnei te whakamātautau ā-mahi e whakamahia ana e ngā kairangahau hei kī he mate ferroptosis tēnei, kaua he mate necrosis noa iho. Mā te titiro whānui ki ngā ara mate pūtau kua whakaritea e kitea ai te horopaki o tēnei rerekētanga. Mā te mōhio ki te whakahaere a ngā pūtau i te rino e wātea ana mō ngā tauhohenga e mārama ai he aha te here-rino i noho ai hei whakamātautau whakatairite tino whakatau.

Te wāhi o ngā mitokōria, me te take i tautohetia ai

I kī ngā rangahau tōmua ka pā tonu te ferroptosis ki ngā pūtau kāore he DNA mitokōria, e tohu ana kāore pea e hiahiatia ana ngā mitokōria. I kitea i ngā rangahau o muri mai, mā te whakaiti i ngā mitokōria, mā te aukati rānei i te tukanga hā pūtau, ka taea te tāmi i te ferroptosis nā te korenga cysteine, engari kāore i te ferroptosis nā te tautāmitanga tōtika o GPX4. Ka taea ēnei hua e rua te tika, mehemea ka whakawhirinaki te wāhi o ngā mitokōria ki te whakaoho, ki te momo pūtau, me te wāhi e puta ai te perohāoratanga whakatau.

I tirohia e te rangahau tūāpapa o tēnei tuhinga taua tautohe mā tētahi pūoko mō tētahi wāhanga motuhake o te pūtau. Ko MitoCLox tētahi putanga o te pūoko perohāoratanga lipidi kua arohia ki ngā mitokōria: ka rerekē tōna kōrekoreko ina tūtaki ia ki ngā tuwhena peroxyl lipidi i roto i ngā mitokōria. I ngā pūtau fibroblast i tukuna ki te erastin, i puta te hāoratanga o te pūoko mitokōria i ngā pūtau e ora tonu ana i mua i te matenga, ā, he rerekē tēnei puta noa i te huinga pūtau. He mea nui taua raupapa wā. He take pea te perohāoratanga ka puta i mua i te mate. Ko te perohāoratanga ka inea i ngā pūtau mate anake he toenga tūkinotanga. Kei tētahi aratohu āpiti mō ngā whakamātautau perohāoratanga lipidi me ngā mea e whakaaturia ana e ia pūoko te whakamārama he aha te wāhi o te pūoko i whakatau ai i te tikanga o tētahi tohu.

I puta taua tauira anō i tētahi tauira whakamātautau tuarua. Ko ngā pūtau fibroblast nō tētahi tūroro whai mate io whatu tuku iho o Leber, e mau ana i tētahi irakētanga o te matatini I me te ahotea hāora teitei ake i te tīmatanga, i mate i te ferroptosis i te whakahekenga o te glutathione, engari i ātete ngā pūtau fibroblast whakatairite. I puta tuatahi anō te hāoratanga o te pūoko mitokōria. Kei te rangahau fibroblast mō te perohāoratanga o ngā lipidi mitokōria i te ferroptosis ngā taipitopito.

Ngā mea i panonitia e te kikorangi metilēne i ēnei whakamātautau

He kaikawe hāora-whakaheke te kikorangi metilēne. Ka tango tōna āhua kua hāoratia i ngā irahiko mai i ngā tauhohenga matū e hono ana ki te NADH i te matatini I, ā, ka tuku tōna āhua kua whakahekea i aua irahiko ki te cytochrome c, e whāngai ana i te matatini IV. Ka hanga tēnei i tētahi ara karo wāhanga mō te wāhanga o te mekameka e turuturu noa ai ngā irahiko ki te hāora hei superoxide. Mō ngā kaipānui e hiahia ana ki te pikitia katoa o te tukunga irahiko, tīmata ki te āhua e nekehia ai ngā irahiko mā ngā mitokōria e te kikorangi metilēne.

I ngā pūtau fibroblast pūkahukahu i tukuna ki te erastin, i pupuri te kikorangi metilēne i te kukūtanga 250 nanomolar i te ora o ngā pūtau, e ai ki tētahi inenga oranga pūtau, pērā anō i ngā matū ārai-hāora e arohia ana ki ngā mitokōria, arā ko SkQ1 me MitoTEMPO. Ko ngā whakamātautau whakatairite e tautuhi ana i te kerēme. I tiaki hoki te ferrostatin-1, te alpha-tocopherol me te deferoxamine, e whakaū ana he mate ferroptosis tēnei. Kāore te matū rite ki SkQ1, engari kāore ōna rōpū ārai-hāora, i tiaki. E tohu ana tēnei ki ngā tauhohenga hāora-whakaheke, kaua ki te whakaeminga kore-motuhake. I memenge te tiakitanga i runga ake i te āhua 200 nanomolar SkQ1, e hāngai ana ki te āhua whakakaha-hāoratanga kua mōhiotia o ngā matū ārai-hāora quinone ina nui ake te rahinga. He āhua horopeta matarua tō te kikorangi metilēne anō: he tiaki i ngā taumata nanomolar iti i ēnei rīhi, engari ka taea te whakaputa hauwai perokita mā te huringa hāora-whakaheke ina whakanuia ake te kukūtanga, ina kaha rānei te whiti o te rama ki runga. Kei ngā momo hāora hohe i ngā mitokōria te kōrero mō tēnei momo horopaki horopeta.

Kātahi ngā whakamātautau mitokōria kua wehea i wehewehe i ngā puna o ngā momo hāora hohe (ROS). I te aroaro o te rino ferrous, nā ngā tïpako e whāngai ana i te matatini I me te rotenone i whakaoho te hāoratanga o te pūoko. Ka aukati te rotenone i tētahi wāhi i muri i te wāhi flavin o te ara irahiko. Nā reira ka noho ngā kaikawe o mua i te āhua kua whakahekea, ā, ka turuturu ngā irahiko ki te hāora mai i te flavin e anga ana ki te wāhanga matrix. Nā ngā tïpako e whāngai ana i te matatini III me te antimycin A i whakaputa te hauwai perokita nui, engari kāore i whakaoho i te perohāoratanga lipidi. He ōrite te tohu ROS tapeke, he rerekē te wāhi, he rerekē te hua. I tāmi takitahi a SkQ1 me te kikorangi metilēne i te perohāoratanga i whakaohohia e te matatini I, me te kore e tāmi i te whakaputanga hauwai perokita tonu. E tohu ana tēnei ka mahi rāua i muri i te hanganga ROS, i te kaupae perohāoratanga lipidi.

Te wāhanga rino nui rawa me te tīwhiri lipofuscin

I tirohia e tētahi rangahau tuarua te pātai mai i te taha rino. I ngā pūtau uaua manawa H9c2 i tukuna ki te ferric ammonium citrate i ngā kukūtanga i raro iho i te millimolar, i puta ngā ROS mitokōria, te perohāoratanga o ngā lipidi mitokōria, kātahi ko te ferroptosis, whai muri ko te whakaeminga o tētahi kano rite ki te lipofuscin i roto i te 24 hāora. Ko te lipofuscin he toenga lipidi me ngā pūmua kua hāoratia, he rino kei roto, ā, ka kōrekoreko noa. Ka whakaemi haere tēnei i te kaumātuatanga. Ko tōna putanga tere i konei e hono ana i te perohāoratanga ohorere nā te rino ki tētahi tohu kaumātuatanga kua roa e mōhiotia ana. I ārai takitahi te kikorangi metilēne i ngā kukūtanga nanomolar me SkQ1 i te perohāoratanga, te mate, me te whakaeminga kano. I whakaū ngā mitokōria manawa kua wehea i taua tauira: nā te rotenone me te rino ferrous i whakaoho te perohāoratanga me tētahi tohu rite ki te kano, ā, i aukati ngā matū e rua i aua mea. Kei te rangahau rino nui rawa i ngā pūtau uaua manawa H9c2 te raupapa katoa. E hāngai ana te taha kano o tēnei kōrero ki te lipofuscin me ngā tohu kaumātuatanga pūtau.

Ngā mea kāore e whakaaturia e ngā whakamātautau oranga pūtau

Ko tētahi inenga oranga pērā i te CellTiterBlue e whakaatu ana e hia ngā pūtau i tētahi rīhi e hohe tonu ana ā-pākia i muri i te tukunga o tētahi whakaoho me tētahi matū tiaki e whakamātauria ana. He whakamātautau tēnei i tētahi tukanga i roto i tētahi pūnaha kua tautuhia. Ehara i te hua maimoatanga. Kāore tētahi o ēnei whakamātautau i tuku horopeta ki tētahi tūroro, i ine i tētahi putanga mate, i whakatau rānei i tētahi awhe haumaru, whaihua o te maimoatanga i roto i te tinana.

E whā ngā herenga me āta whakapuaki. Tuatahi, he whāiti ngā momo pūtau: ngā pūtau fibroblast pūkahukahu kua panoni, ngā pūtau fibroblast kiri taketake, tae atu ki tētahi rārangi pūtau whai mate mitokōria, me tētahi rārangi pūtau uaua manawa kiore, me ngā mitokōria manawa kiore kua wehea. He rerekē te tairongo o ia rārangi, ā, i kōwhiria te rārangi LHON nā tōna whakaraerae nui ake i te tikanga. Tuarua, he tino whakaoho taiwhanga ēnei: te aukatitanga katoa o te kawe, o te waihangatanga rānei, me ngā rahinga rino kāore rawa tētahi kiko e pāngia ohoreretia ai. Tuatoru, kāore e taea te huri i te kukūtanga hei horopeta mā te whakarea noa. Ehara te kukūtanga nanomolar i te wē whakatipu pūtau i te horopeta tangata. Ko te tohanga o te kikorangi metilēne, tōna whakahekenga ki tōna āhua kore-tae i te toto me ngā kiko, te pānga o te rama, me te pūmanawa hiko o te kiriuhi, he āhuatanga katoa kei waenga i te rīhi me te tangata. Tuawhā, ka whakaatu ngā pūoko i tō rātou ake wāhanga o te pūtau. Ka whakaatu te hāoratanga MitoCLox i te hanganga o ngā tuwhena lipidi mitokōria; kāore e whakaatu i āraia tōtikatia te pakarutanga o te kiriuhi waho o te pūtau, te takahanga whakamutunga pea, kaua kē i karohia mā te aukati i tētahi kaupae o mua.

Nō reira, ko te kerēme pono tēnei: i ēnei tauira, ko ngā ROS nō te matatini I me te rino e whakaoho ana i te perohāoratanga o ngā lipidi mitokōria i mua i te ferroptosis, ā, ka haukoti te kikorangi metilēne i ngā kukūtanga iti i taua wāhanga. Mō ngā mea kei tua atu i taua wāhanga, me whai whakamātautau kē i ngā kararehe, kātahi i te tangata.