In 1437, amidst intense discussions about the Union of the Catholic and Orthodox Churches, Joseph II, the Patriarch of Constantinople, appointed Isidore, a cleric from Thessalonica who supported the Union, as Metropolitan of Kyiv and all Rus’, a position that, since 1325, had been based in Moscow. Isidore would become the last Greek spiritual leader of Rus’.  

Following his appointment, Isidore traveled to Moscow but stayed only a few months before heading to Italy for the Council of Ferrara-Florence. The council's objective was to achieve the Union of the Churches, which was officially proclaimed on July 6, 1439, with the signing of the papal bull Laetentur coeli. The declaration, made in the presence of Byzantine Emperor John VIII Palaiologos and Pope Eugene IV, affirmed the reunification of the Roman and Greek Churches. Isidore was among the signatories and was appointed cardinal at the council.  

After these events, Isidore returned to Moscow, where, on Palm Sunday, March 22, 1441, he conducted a service in the Dormition Cathedral of the Kremlin, reading the act of Union and offering a prayer for the Pope. He then participated in a procession through the city alongside Grand Duke Vasily II, carrying a large Latin cross.  

Only three days later, however, Isidore was arrested by Vasily, who had been influenced by the local clergy’s strong opposition to the Union. Accused of apostasy, he was imprisoned. In response, Moscow requested permission from the new pro-Union Patriarch of Constantinople, Metrophanes of Cyzicus, to elect its own Metropolitan independently, but this request was denied. Defying this rejection, in 1443, the Russian episcopal synod proceeded with the autonomous election of Isidore’s rival, Jonah, effectively ending Moscow’s administrative dependence on Constantinople and initiating the process that would soon lead to its ecclesiastical autocephaly.  

What became of Isidore? After his release from imprisonment, he traveled to the "Second Rome", Constantinople, where he was present when the city fell to the Turks in 1453. Following this event, he fled once again, this time to Rome, where he lived until his death in 1463.