Piezo1-mitochondrial calcium coupling in mechanotransduction, mitochondrial stress, and cell fate

Piezo1-derived Ca²⁺ signals provide a mechanosensitive route through which mechanical inputs are decoded by mitochondria. Piezo1 converts membrane tension, fluid shear stress, and matrix stiffening into ionic signals, but mitochondrial outcomes depend on how Ca²⁺ is spatially routed, buffered, and amplified. This review integrates plasma membrane-initiated entry, endoplasmic reticulum (ER)-mitochondria communication, voltage-dependent anion channel (VDAC)/mitochondrial calcium uniporter (MCU)-related transfer, cytoskeletal organization, and selected organelle-associated Piezo1 signals. We examine how mechanical dose, pathological microenvironments, and cell state shift mitochondrial decoding from adaptive bioenergetic, redox, and quality-control responses toward Ca²⁺ overload and organelle failure. A shared mitochondrial stress state can then bias apoptosis, ferroptosis, inflammatory death, or senescence, producing tissue-specific outcomes and therapeutic opportunities. The translational goal is not indiscriminate Piezo1 blockade, but restoration of a safe coupling range between Piezo1-derived Ca²⁺ entry and mitochondrial buffering, repair, and fate stability.