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Developmental Biology - Mitochondria
Mitochondrial Fusion
Better together! Mitochondrial fusion supports cell division...
Mitochondria are the powerhouses of the cell. New research from Washington University in St. Louis shows that when cells divide rapidly, their mitochondria fuse together. In this configuration, a cell uses oxygen more efficiently for energy. Fused mitochondria also produce a biochemical byproduct — aspartate — key to cell division.
The lab of Gary Patti PhD, the Michael and Tana Powell Associate Professor of Chemistry in Arts & Sciences, reported their work in the journal eLife. It shows how mitochondria combine to help cells multiply in unexpected ways.
As cancer cells are known to divide at a runaway pace, these new findings may help in cancer diagnosis and treatment.
"Most studies of proliferating cells are conducted in the context of cancer, where scientists are comparing a cancer tissue that's rapidly growing with normal tissue that surrounds the tumor or a normal tissue from a different patient," said Conghui Yao, a PhD candidate in Patti's lab at Washington University and first author of the new study. "These kinds of comparisons are physiologically relevant but have some disadvantages.
"A tumor is very complicated. Not only because it is made up of different kinds of cells, but also because the environment of a tumor is different from that of healthy tissue," she adds. A tumor needs nutrients to grow, but doesn't have the blood vessel infrastructure typical of other healthy tissue. As a result, tumors are often starved for oxygen. Even in the presence of abundant oxygen, cancer cells get energy through a less efficient fermentation process.
Instead of using oxygen to burn glucose in their mitochondria, cancer cells use an "aerobic glycolysis" process that turns glucose into lactate — a process called the Warburg effect.
Although the Warburg effect has been observed in rapidly dividing cells for more than 90 years, it still isn't fully understood. The earliest explanations suggested that mitochondria in cancer cells are damaged in a way that prevents them from producing energy normally. Yao is familiar with the Warburg effect and its implications. So she set up an experimental system to allow her to turn cell division on and off, and was surprised to see dividing cells consumed a lot of oxygen.
"Much of the literature had suggested dividing cells would do the opposite," says Yao. "So we looked into not only why our dividing cells were consuming more oxygen, but also how they were able to consume more oxygen." Part of the beauty of Yao's initial experiment was its simplicity. She was able to measure metabolism in one specific type of cell under two distinct conditions - when the cell was dividing and when it was not dividing. That's also how she was able to hone in on the particular structural change to mitochondria which was driving the efficiencies she observed.
"Dividing cells had the same amount of mitochondria per protein or per mass, compared to non-dividing cells. But, we noticed these dividing cells were significantly longer."
Gary J. Patti PhD, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Longer because adjacent mitochondria had fused into one - making multiple, adjoined mitochondria into bigger, more efficient, energy-generating machines. Yao discovered another surprise. These "mega-mitochondria" were particularly good at creating a molecule called aspartate, essential for cells replication. "Recent work from other labs had taught us that one of the most important reasons dividing cells need to consume oxygen is to make aspartate. So it made sense that mitochondrial fusion in dividing cells would increase aspartate levels," explains Yao.
Yao and Patti are not the first to observe mitochondrial fusion. But, they are among the first to interrogate mitochondrial fusion with metabolomic technology — a process that can target malignant cancer cells.
Patti: "It is often said that rapidly dividing cancer cells increase fermentation at the expense of decreasing oxygen consumption for mitochondrial activity. Our results suggest that at least some rapidly dividing cells increase both processes under normal oxygenated conditions. Since use of nutrients by rapidly dividing cancer cells is the basis for various drugs and diagnostic tests, these findings may have important clinical significance — and may represent a metabolic vulnerability in cancer."
Abstract
Proliferating cells often have increased glucose consumption and lactate excretion relative to the same cells in the quiescent state, a phenomenon known as the Warburg effect. Despite an increase in glycolysis, however, here we show that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by ~30% during proliferation. Both increases are supported by mitochondrial fusion. Impairing mitochondrial fusion by knocking down mitofusion-2 (Mfn2) was sufficient to attenuate proliferation, while overexpressing Mfn2 increased proliferation. Interestingly, impairing mitochondrial fusion decreased OXPHOS but did not deplete ATP levels. Instead, inhibition caused cells to transition from excreting aspartate to consuming it. Transforming fibroblasts with the Ras oncogene induced mitochondrial biogenesis, which further elevated OXPHOS. Notably, transformed fibroblasts continued to have elongated mitochondria and their proliferation remained sensitive to inhibition of Mfn2. Our results suggest that cell proliferation requires increased OXPHOS as supported by mitochondrial fusion.
Authors
Cong-Hui Yao, Rencheng Wang, Yahui Wang, Che-Pei Kung, Jason D Weber and Gary J Patti.
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Mar 28 2019 Fetal Timeline Maternal Timeline News
 Schematic of the metabolic differences between quiescent and proliferating fibroblasts. The increase in OXPHOS is supported by mitochondrial fusion. Image: eLife
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