Junichiro Hironaka's office issued a brief statement saying they had "filed with the Tokyo District Court letters of resignation for all lawyers... connected with all cases related to Mr Carlos Ghosn".
Hironaka, 74, who earned his nickname for sharp legal strategies and an enviable acquittal record, has said he was "dumbfounded" by Ghosn's escape, which he discovered via the media on the morning his client fled.
Another one of Ghosn's legal team, Takashi Takano, has also thrown in the towel on the case, a source close to his office told AFP.
Hiroshi Kawatsu, the third man in the legal "dream team" assembled by the former Nissan boss, has not publicly commented on his plans and could not be immediately reached for comment.
The resignations came after Ghosn smuggled himself out of Japan last month to Lebanon in an elaborate escape that humiliated Japan's law enforcement officials and his defence lawyers.
It was the latest twist in a saga that has captivated the automotive industry ever since November 2018 when Ghosn was arrested at a Tokyo airport after a team of prosecutors stormed onto his private jet.
He spent 130 days in detention and faced multiple financial misconduct charges in Japan.
The tycoon has denied all the charges and claimed he was a victim of a plot by Nissan and Japanese officials.
Ghosn is believed to have left Japan by hiding in a large case for audio equipment on a private jet, aided by a team of operatives.
In Lebanon, he gave a major press conference and a series of media interviews in a bid to clear his name. He also lashed out at Japan's judicial system, claiming he felt he would not receive a fair trial in Tokyo.
Legal cases are continuing against Nissan and Ghosn's right-hand man Greg Kelly, who faces related financial misconduct charges.
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