Mammalian mitochondria are emerging as a critical stress-responsive contributor to cellular life/death and developmental outcomes. Maintained as an organellar network distributed throughout the cell, mitochondria respond to cellular stimuli and stresses through highly sensitive structural dynamics, particularly in energetically demanding cell settings such as cardiac and muscle tissues. Fusion allows individual mitochondria to form an interconnected reticular network, while fission divides the network into a collection of vesicular organelles. Crucially, optic atrophy-1 (OPA1) directly links mitochondrial structure and bioenergetic function: when the transmembrane potential across the inner membrane (ΔΨm) is intact, long L-OPA1 isoforms carry out fusion of the mitochondrial inner membrane. When ΔΨm is lost, L-OPA1 is cleaved to short, fusion-inactive S-OPA1 isoforms by the stress-sensitive OMA1 metalloprotease, causing the mitochondrial network to collapse to a fragmented population of organelles. This proteolytic mechanism provides sensitive regulation of organellar structure/function but also engages directly with apoptotic factors as a major mechanism of mitochondrial participation in cellular stress response. Furthermore, emerging evidence suggests that this proteolytic mechanism may have critical importance for cell developmental programs, particularly in cardiac, neuronal, and stem cell settings. OMA1’s role as a key mitochondrial stress-sensitive protease motivates exciting new questions regarding its mechanistic regulation and interactions, as well as its broader importance through involvement in apoptotic, stress response, and developmental pathways.

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The bioenergetic function of mitochondria is linked to its organellar structural dynamics by optic atrophy‐1 (OPA1), a nuclear‐encoded protein that mediates fusion of the mitochondrial inner membrane. OPA1‐mediated inner membrane fusion is dependent on the transmembrane potential across the mitochondrial inner membrane (Δψm): long (L‐OPA1) isoforms accomplish fusion for an interconnected reticular morphology when Δψm is intact. Upon loss of Δψm, L‐OPA1 is cleaved by the OMA1 metalloprotease, causing accumulation of short S‐OPA1 and collapse of mitochondrial fusion to a fragmented morphology. We examined Δψm‐sensitive mitochondrial fusion in human AC16 cardiomyocytes treated with carbonyl cyanide m‐chlorophenyl hydrazone (CCCP), an uncoupler of Δψm. Upon increasing titration with CCCP, mitochondrial fusion collapses at [CCCP] > 2 μM, as determined using blinded ImageJ quantification of mitochondrial morphology. Similarly, OPA1 Western blotting revealed that AC16s show a significant loss of fusion‐active L‐OPA1 at [CCCP] > 2 μM. Taken together, these findings indicate that L‐OPA1 maintains mitochondrial fusion, but that OMA1 is activated at [CCCP] > 2 μM, causing L‐OPA1 cleavage and collapse of mitochondrial fusion. Experiments in progress are examining OMA1 activation at this Δψm breakpoint, as well as impact of altered OPA1 and OMA1 expression. Support or Funding Information NIGMS 5SC3GM116669 (to R.G.)NIGMS 1SC3GM132053 (to M.K.)UTRGV Presidential Graduate Research Assistantship (to P. D.)