Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer

Abstract

Metabolism describes the life-sustaining chemical reactions in organisms that provide both energy and building blocks for cellular survival and proliferation. Dysregulated metabolism leads to many life-threatening diseases including obesity, diabetes, and cancer. Mitochondria, subcellular organelles, contain the central energy-producing metabolic pathway, the tricarboxylic acid (TCA) cycle. Also, mitochondria exist in a dynamic network orchestrated by extracellular nutrient levels and intracellular energy needs. Upon stimulation, mitochondria undergo consistent interchange through fusion (small to big) and fission (big to small) processes. Mitochondrial fusion is primarily controlled by three GTPases, mitofusin 1 (Mfn1), Mfn2, and optic atrophy 1 (Opa1), while mitochondrial fission is primarily regulated by GTPase dynamin-related protein 1 (Drp1). Dysregulated activity of these GTPases results in disrupted mitochondrial dynamics and cellular metabolism. This review will update the metabolic roles of these GTPases in obesity, diabetes, and cancer.

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

“…Mdivi-1 (a widely accepted DRP1 inhibitor) induced cancer cell death and decreased tumour size in xenograft models. 4,19 Mdivi-1 increased OCR in non-cancer cells like mouse neuroblastoma 58 but deceased OCR in human ductus arteriosus smooth muscle cells. 59 Similar to these findings, studies showed that mdivi-1 increased OCR in some cancer cells 60,61 but decreased OCR in other cancer cells.…”

“…15,16 Mitochondrial fusion and fission contribute to these morphologic changes and are often dysregulated under pathological conditions, including cancers. 18,19,25,28,51 Most studies of cancer-related mitochondrial dynamics focus on their function in apoptosis, [52][53][54] and elevated mitochondrial fission has been linked to impaired oxygen consumption in cancer cells. 18,[55][56][57] However, it is not clear whether mitochondrial dynamics regulate metabolic alterations in cancer.…”

“…30 Studies showed that mdivi-1 treatment altered mitochondrial morphology and cellular oxygen consumption, induced cell death in cancer cells, and limited tumour size in xenograft models. 4,19 However, a recent study showed that mdivi-1 failed to elongate mitochondria or inhibit recombinant human DRP1 GTPase activity in mouse embryonic fibroblasts (MEFs) and normal neurons, and mdivi-1 reversibly inhibited respiration at mitochondrial complex I to decrease the oxygen consumption rate (OCR). 31,32 Also, in Candida albicans, mdivi-1 phenotypic effects were independent of DNM1 (analogue of DRP1).…”

An indispensable role for dynamin-related protein 1 (DRP1) in adipogenesis

“…Mitochondrial dynamics play a pivotal role in diverse cellular processes, such as adipocyte differentiation, lipid homeostasis, and oxidative metabolism. Adipose tissue mitochondrial dysfunction contributes significantly to the pathogenesis of obesity-associated metabolic diseases (Cedikova et al, 2016;Chouchani & Kajimura, 2019;Dai & Jiang, 2019;Lee et al, 2019).…”

“…Obesity and other metabolic diseases are associated with adipose tissue dysfunction and attenuated beigeing and browning efficiencies (Dai & Jiang, 2019). However, the molecular mechanisms are not completely understood.…”