Te kikorangi methylene, Nrf2, me te hanga mitokōria hou: ngā mea i ine, me ngā mea he whakapae tonu

He rerenga kōrero kotahi e kitea nuitia ana i ngā tuhinga mō te kikorangi methylene: ka whakahohe tēnei i te Nrf2, ā, ka hanga mitokōria hou. He rite te pānuitanga o te rerenga ki tētahi kerēme kotahi, engari e rua ngā ariā rerekē kei roto, kua rangahaua i roto i ngā pūnaha rerekē, mā ngā momo taunakitanga rerekē. Ko te tuatahi he ara tuku tohu, he pūoko e whakahohe ana i ngā ira whakamarumaru. Ko te tuarua he hōtaka hanga, arā, ko te pūtau e hanga ana i ētahi atu taputapu mitokōria. Ka taea e tētahi tohu te tīmata i te hanga, engari ko te whakaatu i puta te tohu, ehara tērā i te whakaatu kua tū te whare; ā, ko te whakaatu kua nui ake ngā rawa hanga, ehara tērā i te whakaatu kua pai ake te tuku pūngao. Ka wehewehea ēnei mea e toru i tēnei tuhinga.

Te ariā Nrf2: he pūoko, ehara i te whakangungu rakau

He tauwehe tuhi ira te Nrf2 (tauwehe 2 e pā ana ki te tauwehe karihi erythroid 2), arā, he pūmua ko tāna mahi he whakahohe i ngā ira. I te wā e noho mārie ana te pūtau, ka puritia tēnei i te wai o te pūtau e tētahi pūmua pūoko e kīia ana ko Keap1. Ka tukuna e Keap1 te Nrf2 ki ngā taputapu whakakore a te pūtau, kia wawahia tonutia. Ina panonitia e ngā matū whakahāora, e ngā matū kukume irahiko rānei, ngā cysteine hohe o Keap1, ka mutu taua whakakore. Ka whakaemi te Nrf2 kātahi anō ka hangaia, ka neke ki te karihi, ka hono ki ngā pūmua Maf iti, ā, ka piri ki ngā raupapa DNA e kīia ana he huānga urupare ārai whakahāoratanga. Mā taua piringa e whakahohe tētahi huinga ira whakamarumaru.

He tauwhāiti ngā inenga tohu matua o tēnei ara. Ko NQO1 (NAD(P)H quinone dehydrogenase 1) me TrxR1 (thioredoxin reductase 1) ētahi o ngā ira whāinga Nrf2 tino pono hei tohu. He ngāwari te whakakaha i te HO-1 (heme oxygenase-1), engari ka urupare hoki ki ētahi atu kaiwhakahaere. He taputapu ārai whakahāoratanga ngā whākōkī pērā i te SOD me te catalase, engari e whakahaerehia ana ō rātou taumata e te maha o ngā tauwehe tuhi ira. Nō reira, kāore te pikinga o te SOD anake e whakaū ko Nrf2 te take. Ko ngā taunakitanga e tino tata ana ki te takahanga tuku tohu, ko te whakaemi Nrf2 ki te karihi, ko te whakahohe i tētahi pūrongo ARE, ko te whakakaha rānei i ngā whāinga matua ka ngaro ina tangohia te Nrf2. Ko ngā mea katoa atu — ngā taumata matū whakahāora iti iho, te pai ake o te ora i raro i te ahotea, te nui ake o te glutathione — he pānga ka puta ki raro i te ara, ā, he maha ngā ara ka taea te whakaputa.

Ko te hua tuatahi mō te kikorangi methylene i tēnei kōrero e hāngai ana ki te pito tata o taua tauine. I ngā pūtau fibroblast i pāngia ki te kikorangi methylene i ngā kukū nanomolar, i kitea te whakaroa o te koroheketanga pūtau, me te nui ake o te matatini IV, te nui ake o te kohi hāora, me te whakakaha i ngā whākōkī wāhanga-2 TrxR1 me NQO1. I pūrongotia ēnei i te rangahau tuatahi i hono ai te kikorangi methylene ki te whakapai ake i ngā mitokōria me te whakaroa i te koroheketanga pūtau. Ko TrxR1 me NQO1 tonu ngā whāinga matua Nrf2 e hiahia ana te kaipānui tūpato kia kite. Ko te mea kāore i whakaaturia e te rangahau, ko te takahanga tuku tohu ake: kāore he inenga Nrf2 i te karihi, kāore he pūrongo ARE, kāore hoki he whakamātautau whakatairite kua whakakorea te Nrf2. Nō reira, ko te whakamāramatanga pono, ka whakakaha te kikorangi methylene i ngā ira e mōhiotia ana he whāinga Nrf2 i tēnei pūnaha. E hāngai ana tēnei ki te whakahohe Nrf2, engari kāore e wehe motuhake i te Nrf2 hei take. Ko te whakakaha i tētahi ira whāinga, he takahanga kotahi i muri i te pana whakahohe.

Te ariā hanga mitokōria hou: he hōtaka me ngā wāhi arowhai e toru

Ko te hanga mitokōria hou te hōtaka e whakapiki ai te pūtau i tōna kaha mitokōria. E ai ki ngā pukapuka ako, e toru ngā wāhi arowhai o tōna raupapa whakahaere. Tuatahi, ka whakakā te kaiāwhina whakahohe PGC-1alpha i te hōtaka. Tuarua, ka kōkiri ngā tauwehe tuhi ira o te karihi i te whakapuakitanga o ngā ira mitokōria, tae atu ki TFAM, e tiaki ana, e tārua ana hoki i te DNA mitokōria. He mea whakararu, ko tētahi o aua tauwehe e kīia ana ko NRF1, te tauwehe manawa karihi 1, he pūmua rerekē tēnei i te Nrf2. Tuatoru, ka nui ake ngā huinga ira mitokōria me ngā taputapu manawa o te pūtau. Ka taea te ine i ēnei mā te maha o ngā tārua mtDNA, te hohe o te citrate synthase, te nui me te hohe rānei o ngā matatini manawa.

He rerekē te kaha o te kerēme ka tautokona e ia wāhi arowhai, tēnā i tō te wāhi o mua. Mā te nui ake o te RNA karere PGC-1alpha, TFAM rānei, e whakaatu kua tonoa te hōtaka, ehara i te mea kua oti. Mā te nui ake o te mtDNA, o te pūmua matatini IV rānei, e whakaatu kua nui ake ngā rawa, engari ka pēnei anō te āhua o ngā mitokōria kua whakahoua. Mā te pai ake o te manawa — te nui ake o te kohi hāora, te hohe rānei o ngā matatini — e whakaatu kua panoni te mahi, engari ka pai ake pea te mahi me te kore rawa e hanga mitokōria hou. Ka whakakotahi te kerēme hanga mitokōria hou kaha i ngā mea e toru katoa: te kaiwhakahaere, te nui o ngā rawa, me te mahi.

I tirohia te nuinga o taua raupapa i te rangahau whai muri mō ngā fibroblast. I ngā pūtau IMR90 tangata i tukuna ki te kikorangi methylene 100 nanomolar, i piki rangitahi te ōwehenga NAD ki NADH i roto i te 15 meneti, ā, i hoki ki te taumata taketake i roto i te rā kotahi. Whai muri i taua tohu pūngao rangitahi, ka tāpirihia rangitahitia he rōpū phosphate ki te pūoko pūngao AMPK. Kātahi ka whakakahangia te PGC-1alpha me te SURF1, he pūmua e hiahiatia ana hei whakahiato i te matatini IV e mahi tika ana. I tata rearua te hohe o te matatini IV, i heke ngā matū whakahāora o te pūtau ki te āhua 28 percent, ā, i pōturi ake te ngau haere o ngā telomere. Kei te tuhinga e hono ana i te hohe redox o te kikorangi methylene ki te AMPK me te hanga mitokōria hou te raupapa katoa.

E rua ngā kōrero taipitopito o taua tuhinga e tika ana kia āta tirohia, nā te mea koinei te momo kōrero ka mahue i te nuinga o te wā. Tuatahi, he nui ake te hiranga o te tauira whakahohe i te noho noa o te whakahohe: i whakakā rangitahi te kikorangi methylene i te AMPK, engari i whakakā mauroa te rongoā whakatairite AICAR i taua pūmua. Ko te kaiwhakahohe rangitahi i whakaroa i te koroheketanga pūtau me te kaha e tata ana ki te waru whakareatanga ake. Nō reira, kāore i oti te kerēme pēnei i te kōrero, "ka whakahohe te kikorangi methylene i te AMPK". Ko te kerēme whai take, ka whakahohe rangitahi tēnei i te AMPK, ā, e tohu ana te whakatairitenga kāore te whakahohe mauroa e mahi pēnei. Tuarua, kāore te kikorangi methylene i panoni i te huringa pūtau. Mā tēnei e whakakore te whakamārama kē tino māmā: arā, i pōturi noa ake te wehenga o ngā pūtau, ā, nā reira i āhua taitamariki ake ai.

Te peka kiore: te whanonga, ngā huinga ira, me tētahi tīmatanga whakahē i te tūmanako

Nā tētahi rōpū e rangahau ana i ngā kiore pakeke-waenga i whakawhānui te mahi whakatipu pūtau ki ngā kararehe. I muri i te 60 rā e whāngaihia ana te kikorangi methylene mā te waha, i mau tonu ki ngā kiore i whiwhi i taua matū te nui ake o tō rātou manawaroa ā-tinana me te whanonga torotoro, ā, he iti iho tō rātou whanonga rite ki te māharahara, tēnā i ngā kiore kaumātua kāore i whiwhi i taua matū. I te kiko roro, ko ngā ira i pēhia e te koroheketanga — NRF1, TFAM, SOD2, me te wāhanga COX1 o te matatini IV — i whakahokia kia tata ake ki ngā taumata o te pakeketanga, ā, i piki te maha o ngā tārua mtDNA. E pūrongotia ana aua hua — te whanonga, te kaiwhakahaere, me te nui o ngā huinga ira — i te rangahau kiore pakeke-waenga mō te kikorangi methylene me te hanga mitokōria hou i te roro.

Ko te tīmatanga e whakapaetia ana te wāhanga whakamere, nā te mea e whakahē ana i te kōrero māmā he matū ārai whakahāoratanga te kikorangi methylene. I ngā kiore i whiwhi i taua matū, i kitea te nui ake o te whakaputa momo hāora hohe i ngā mitokōria roro, otirā te hauwai peroxide. Ko te whakapae a ngā kaituhi: he tohu peroxide māmā te mea e whakahohe ana i te ara Nrf2, ā, mā taua ara e kōkiri te hōtaka hanga mitokōria hou. I tēnei tauira, he matū whakatairanga whakahāoratanga te kikorangi methylene i te takahanga tīmata, ā, he matū ārai whakahāoratanga i te takahanga hua. Ka kīia tēnei tauira e ngā mātanga mātai rongoā he hormesis: mā tētahi ahotea iti e whakaoho he whakamarumaru nui ake i te ahotea ake. Kāore i whakamātauria hāngaitia mēnā nā taua pikinga peroxide tonu i whakahohe te Nrf2; koinei te hononga e whakapaetia ana, ehara i te hononga kua ine.

I whakamātauria e tētahi rangahau āpiti nō taua rōpū anō te taha haumaru o taua whakapae i raro i ngā āhuatanga whakawero. I ngā mitokōria roro kua wehea, i whakapiki te kikorangi methylene i te whakaputa hauwai peroxide i ngā kukū iti iho ki te 50 nanomolar. Heoi, i ngā kukū whakamahinga haumanu, kāore he tūkino i te DNA mitokōria i kitea. I te 100 micromolar anake, he kukū tino teitei ake i ngā taumata whakamahinga haumanu, i kitea he tūkino i ētahi wāhanga mtDNA kua tīpakohia. Nā te whakakotahitanga o te waikano 20 micromolar me te rama whero i whakaputa te hāora singlet, i whānui ai te tūkino i te mtDNA. Koinei te whanonga mōhiotia o te waikano hei kaiwhakahohe mā te rama, ehara i tōna mahi rongoā i te pōuri. I tua atu, nā te tuku i te matū i mua i whakamarumaru ngā mitokōria o te taha whakararo o te roro waenga i ngā wharanga mtDNA nā te rotenone. Kei te rangahau mō te whakaputa peroxide a te kikorangi methylene me te kore tūkino ira ngā taipitopito o te urupare ki te nui o te matū me ngā whakamātautau whakatairite mō te tūkino ira.

Ngā mea kua ine me ngā mea e whakapaetia ana: te pānui i te hoahoa

I tāngia te hoahoa ara kei raro nei mō tēnei tuhinga, hei whakapūmau i te wehewehenga kua mahia e ngā kōrero. Ko ngā pouaka whai taitapa rārangi mārō he takahanga e tautokona hāngaitia ana e ngā whakamātautau i ngā tuhinga rangahau mō te kikorangi methylene: te huringa redox e neke ai te NAD/NADH, te tāpiri phosphate rangitahi ki te AMPK, te whakakaha i te PGC-1alpha me te SURF1, te nui ake o te hohe matatini IV, te whakakaha i te NQO1 me te TrxR1, te whakahokinga o te whakapuakitanga o ngā ira hanga mitokōria hou me te maha o ngā tārua mtDNA i te roro kiore, me te pikinga peroxide kāore e tūkino i te mtDNA i ngā nui whakamahinga haumanu. Ko ngā pouaka whai taitapa rārangi motumotu ngā hononga e whakapaetia ana: ko Keap1 e rongo ana i te tohu peroxide, ko te whakaemi Nrf2 ki te karihi e kōkiri ana i ngā ira whakamarumaru, me te pere take–hua mai i te whakahohe Nrf2 ki te hōtaka hanga mitokōria hou. He whaitake aua takahanga motumotu, he hāngai ki ngā raraunga, ā, he koiora noa e whakaakona ana i ngā pukapuka ako. Engari, i ēnei tuhinga, kāore i ine mā ngā whakamātautau whakatairite — te Nrf2 i te karihi, ngā pūrongo ARE, te whakakore Nrf2 — e tika ana hei huri i aua pouaka ki ngā pouaka rārangi mārō.

E toru ngā rangiruatanga ka mārama ina kei mua i a koe te hoahoa. Tuatahi, he pūmua rerekē a NRF1 rāua ko Nrf2, ahakoa he tata ōrite ngā ingoa. I ine te rangahau kiore i te tauwehe manawa karihi 1, he kaiwhakahaere hanga mitokōria hou, kaua i te tauwehe tuhi ira ārai whakahāoratanga. Mā te pōhēhē he mea kotahi ēnei e kōpeke te hoahoa katoa ki tētahi kōpuku kotahi. Tuarua, ko te whakapuakitanga ira te tīmatanga o te kōrero, ehara i te mutunga. Ko te whakahokinga o ngā RNA karere TFAM, COX1 rānei, e tautoko ana i te tono hanga mitokōria hou, engari ko te maha o ngā tārua mtDNA me te hohe matatini IV ngā taunakitanga kua whakatutukihia te tono. Tuatoru, kāore te hua ārai whakahāoratanga e whakaū i te ara Nrf2. Ko te hekenga 28 percent o ngā matū whakahāora i ngā fibroblast me te whakamarumaru i te rotenone i ngā kiore, he pānga tūturu kei raro i te ara, engari he maha ngā ara e ahu atu ana ki aua pānga.

Ngā mea hei huri i tētahi pouaka motumotu ki te pouaka mārō

He whakamātautau paerewa ngā whakamātautau e ngaro ana. Mā te ine i te pūmua Nrf2 i te karihi i muri i te pānga ki te kikorangi methylene, me te raupapa wā e hāngai ana ki te tohu rangitahi AMPK, e whakamātau mēnā ka whakahohe ngātahi tonu ngā peka e rua, e ai ki te whakapae whakahohe tukutahi. Mā tētahi pūrongo e kōkirihia ana e te ARE e whakaū te hohe tuhi ira, kaua e whakatau noa mai i ngā ira whāinga. Mā te whakahoki i ngā inenga hanga mitokōria hou me te Nrf2 kua whakaitihia, kua whakakorea rānei, e whakamātau hāngaitia te pere take–hua: ki te mau tonu te whakakaha matatini IV me te pikinga mtDNA ahakoa kāore he Nrf2, e hē ana te hononga, ā, ko te peka AMPK anake e kawe ana i te pānga. I te taha kararehe, mā tētahi rangahau tuku matū mauroa, me aua wāhi arowhai e toru anō — te kaiwhakahaere, te nui o ngā rawa, te mahi — e whakamātau mēnā ka noho whakakā tonu te hōtaka, ka urutau rānei. Kia tae rā anō ki taua wā, ko te whakahohe tukutahi o ngā ara pūngao me ngā ara whakamarumaru e noho tonu ana hei tā ngā kaituhi i kī ai: he take matua pea, ehara i te tikanga mahi kua whakaūngia.

Ka hiahia pea ngā kaipānui nō te ao whānui o te mātai rongoā ki ngā horopaki e karapoti ana: te kawe irahiko a te kikorangi methylene i te taumata mitokōria, āna mahi atu ki ngā mitokōria me te pūngao pūtau, te wāhi o ngā kitenga koroheketanga pūtau i roto i te rangahau koroheketanga, te hononga o ngā kerēme hanga mitokōria hou ki te āheinga hinengaro, me ngā taunakitanga haumaru e whakatakoto ana i ngā rohe mō ia kōrerorero mō te nui o te matū ka tukuna. He ariā motuhake ia mea, me ōna ake taunakitanga, ā, e tika ana kia āta wehea mō ia mea ngā mea kua ine i ngā mea e whakapaetia ana, pērā i tā tēnei tuhinga i mahi ai mō Nrf2.