ABSTRACT Two million Americans are hospitalized for sepsis each year, and 1 in 3 die. Those that survive, however, are not cured. Neurocognitive disorders occur in up to 50%, and cognitive decline continues for up to 8 years. Sepsis hospitalizations account for a higher proportion of unplanned readmissions than those for myocardial infarction, heart failure, and COPD. Five-year mortality for sepsis survivors exceeds that for heart failure and stroke. The mechanisms underlying this persistent loss of health remain to be defined. We hypothesize that early during sepsis the mitochondrion is restructured as an adaptive mechanism to protect the cell against any future environmental stress, such as recurrent sepsis. These structural changes impart lasting alterations to the mitochondrial calcium (Ca2+) homeostasis and metabolism necessary to support a cellular phenotype, which for a multicellular organism are poorly tolerated and underlie a persistent loss of health. Our lab has spent nearly two decades studying sepsis to elucidate the Ca2+-dependent mechanisms that regulate mitochondrial biology to balance Ca2+ homeostasis and ATP generation and preserve cellular health. We have shown that early after sepsis, mitochondrial depolarization generates a Ca2+ signal. Members of the family of Ca2+ /calmodulin-dependent protein kinases (CaMK) transduce these Ca2+ signals and work in tandem to mediate adaptive changes in mitochondrial fission, mitophagy, and oxidative metabolism to lessen cellular damage. More recently, we observed that sepsis restructures the mitochondrial calcium uniporter (MCU) complex, imposing long-lasting changes to mitochondrial and cellular Ca2+ homeostasis and metabolism that perturb cellular and tissue function across the entire organism. We propose that as a ‘learned’ response to sepsis, the cell restructures the MCU complex to counter the potential for Ca2+ overload with future insult; this imparts long-lasting alterations in Ca2+ homeostasis, oxidative metabolism, and tissue phenotype. Using models of lower-respiratory tract and intraperitoneal infection and correlative human samples, we propose the following aims: Aim 1. To study in mice and humans how a restructured MCU complex alters Ca2+ homeostasis and oxidative metabolism and thereby, the phenotype of each tissue comprising the organism. Aim 2. To define the mechanisms of mitophagy and protein degradation through the lysosome and proteasome as underlying causes of the persistent loss of MICU1 expression in murine models of sepsis and in human sepsis survivors. This new experimental work will provide foundational knowledge as to how the mechanisms governing mitochondrial Ca2+ and metabolism are restructured during sepsis to underlie a persistent loss of cellular phenotype that leads to a progressive loss of health and shortened survival.