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This broader perspective need not dampen enthusiasm for targeted mitochondrial approaches, which are still in their infancy, but could instead accelerate the translation of such approaches by recognizing the complexity of how such strategies act within the wider cellular context, and alongside existing, successful therapeutic approaches, particularly SGLT2i (whose mechanisms of action in HF remain unresolved despite their clear benefits in both major HF phenotypes)

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Zheng H, Jiang L, Tsuduki T, Conrad M, Toyokuni S

2005 doi: 10.1177/0885066604271616

Under physiological conditions, the Neh2 structural domain of Nrf2 binds to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, facilitating Nrf2 ubiquitination and subsequent degradation (32)