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Review
. 2024 Jul 1;33(4):405-413.
doi: 10.1097/MNH.0000000000000986. Epub 2024 Apr 4.

Mitochondrial bioenergetics: coupling of transport to tubular mitochondrial metabolism

Yong-Yao W Cheng  1 , Chih-Jen Cheng  1   2
Affiliations
Review

Mitochondrial bioenergetics: coupling of transport to tubular mitochondrial metabolism

Yong-Yao W Cheng et al. Curr Opin Nephrol Hypertens. .

Abstract

Purpose of review: Renal tubules have robust active transport and mitochondrial metabolism, which are functionally coupled to maintain energy homeostasis. Here, I review the current literature and our recent efforts to examine mitochondrial adaptation to different transport activities in renal tubules.

Recent findings: The advance of extracellular flux analysis (EFA) allows real-time assessments of mitochondrial respiration, glycolysis, and oxidation of energy substrates. We applied EFA assays to freshly isolated mouse proximal tubules, thick ascending limbs (TALs), and distal convoluted tubules (DCTs) and successfully differentiated their unique metabolic features. We found that TALs and DCTs adjusted their mitochondrial bioenergetics and biogenesis in response to acute and chronic alterations of transport activity. Based on the literature and our recent findings, I discuss working models and mechanisms underlying acute and chronic tubular adaptations to transport activity. The potential roles of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), AMP-activated protein kinase (AMPK), and uncoupling protein 2 (UCP2) are discussed.

Summary: Mitochondria in renal tubules are highly plastic to accommodate different transport activities. Understanding the mechanisms may improve the treatment of renal tubulopathies.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Extracellular flux analysis for isolated renal tubules. (a) In renal tubules, most oxygen consumption occurs in mitochondria, and protons are produced from lactic acids in glycolysis and CO2 in OXPHOS. Different combinations of ETC complexes or substrate metabolism inhibitors (highlighted with bold letters) can be sequentially added in EFA assays to test mitochondrial respiration, glycolysis, and substrate oxidation. (b) When ETC complex inhibitors suppress OXPHOS (top figures), renal tubules with significant glycolysis capacity, like TALs and DCTs, have ECRs increased simultaneously (middle figures). In contrast, like proximal tubules (PTs), renal tubules without much glycolysis capacity show no compensatory ECAR increase after OXPHOS inhibition (bottom figures). The left figures illustrate the concept, and the right figures are examples of actual data. (c) Top figures, renal tubules with high reliance on glucose oxidation in the basal state show a significant OCR reduction after UK5099 injection and no further OCR reduction after the subsequent BPTES/etomoxir injection. Bottom figures: Uncoupler FCCP is used to enhance oxygen consumption and substrate oxidation, mimicking a high-demand state. Renal tubules depending on glucose oxidation for ATP production in a high-demand state show a significant reduction in basal respiration and maximal mitochondrial capacity after UK5099 injection compared to vehicle injection. (d) The sequential injections of ETC complex inhibitors and uncoupler FCCP reveal basal and ATP-linked mitochondrial respiration and maximal & spare (or reserved) mitochondrial capacity. CPT, carnitine palmitoyltransferase 1; EFA, extracellular flux analysis; IMM, inner mitochondrial membrane; MPC, mitochondrial pyruvate carrier; OMM, outer mitochondrial membrane.
FIGURE 2.
FIGURE 2.
Mechanisms of mitochondrial adaptation to acute alteration of transport activity. Acute alteration of transport activity temporarily changes ADP level (and/or ADP/ATP ratio), thus regulating ATP synthase (ETC complex V) turnover rate. Intramitochondrial ATP binds to and inhibits cytochrome c oxidase (ETC complex IV) and OXPHOS when the intramitochondrial ATP/ADP ratio increases. The availability of NAD+, Pi, and energy substrates may regulate short-term ATP balance. ANT, adenine nucleotide translocase; IMM, inner mitochondrial membrane; NAD+, nicotinamide adenine dinucleotide; OMM, outer mitochondrial membrane; Pi, orthophosphate.
FIGURE 3.
FIGURE 3.
Proposed mechanisms of mitochondrial adaptation to chronic alteration of transport activity. (a) Chronic gain-of-function (GOF) renal tubules (left) have sustained high ATP consumption, which causes negative ATP balance when the reserved mitochondrial capacity is exceeded. The reduced cytoplasmic ATP pool triggers chronic mitochondrial adaptations to increase mitochondrial respiratory capacity and normalize intracellular energy balance, and vice versa to chronic loss-of-function (LOF) renal tubules (right). (b) The high energy demand of chronic GOF tubules reduces the cytoplasmic pool of ATP, NAD+, or other substrates to stimulate the AMPK-PGC-1α pathway, which increases mitochondrial respiratory capacity through different mechanisms. In contrast, the low energy demand of chronic LOF tubules increases the energy pool, resulting in reduced mitochondrial mass and less efficient OXPHOS via suppressing the AMPK-PGC-1α pathway and enhancing UCP2 activity.
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