A bacterial enzyme targeted to mouse mitochondria increased energy expenditure, strength, and glucose tolerance
A bacterial enzyme targeted to mouse mitochondria increased energy expenditure, strength, and glucose tolerance
On August 19, Science Advances published a study of LplA, an enzyme from the bacterium Escherichia coli. The authors targeted it to the mitochondria of worms and male mice. In 20-month-old mice, energy expenditure increased, while animals expressing LplA performed better in functional tests of rotarod performance, grip strength, and glucose tolerance.
LplA attaches lipoic acid to proteins. This chemical modification is required by three enzyme complexes in mitochondria. The first transfers a product of glucose breakdown into the energy-producing cycle, the second carries the cycle forward, and the third processes branched-chain amino acids. To place the enzyme near these targets, the authors added a mitochondrial targeting sequence.
In 2019, researchers found that mitochondrial lipoylation, which is the attachment of lipoic acid to proteins, declines together with fuel oxidation in the brown adipose tissue of aged mice. In 2025, coauthors of the current paper showed that LplA increases lipoylation in mammalian cells. The new study tested whether changes in this chemical modification produce functional changes at the level of the whole organism.
The researchers first traced this sequence of effects in worms. LplA increased lipoylation, the activity of one of the complexes, mitochondrial respiration, and carbon flux from labeled glucose. The authors then used RNAi, which temporarily suppresses the activity of a selected gene, to reduce the expression of each of the three target genes in turn. Under these conditions, LplA no longer increased respiration or the difference in electrical charge across the mitochondrial membrane. When the enzyme was activated in adult worms on the sixth day of life, the animals moved faster by the eleventh day and tolerated heat and oxidative stress for longer. Lifespan did not change in this experiment.
Male mice received an adeno-associated virus, which served as a carrier for the genetic instructions, at 4, 10, or 18 months of age and were examined two months later. In 20-month-old animals, metabolic monitoring showed greater oxygen consumption, carbon dioxide production, and energy expenditure. Mice expressing LplA performed better on the rotarod and had greater grip strength, better glucose and insulin tolerance, less collagen deposition in heart and quadriceps muscle sections, and less fat in the liver.
The authors therefore tested the sequence from a chemical modification of proteins to measurable functions of the organism. They used genetic controls in worms and evaluated male mice after gene delivery of LplA.